Modulators of Complement Factor B

Abstract

The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.

Claims

1-94. (canceled)

95. A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 440 or SEQ ID NO: 455, or consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 598, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5 wing segment consisting of five linked nucleosides for SEQ ID NO: 440 and SEQ ID NO: 455, or three linked nucleosides for SEQ ID NO: 598; and a 3 wing segment consisting of five linked nucleosides for SEQ ID NO: 440 and SEQ ID NO: 455, or three linked nucleosides for SEQ ID NO: 598; wherein the gap segment is positioned between the 5 wing segment and the 3 wing segment, wherein each nucleoside of each wing segment of SEQ ID NO: 440 and SEQ ID NO: 455 comprises a 2O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine; and for SEQ ID NO: 598, the 5 wing segment comprises a 2O-methoxyethyl sugar, 2O-methoxyethyl sugar, and cEt sugar in the 5 to 3 direction; wherein the 3 wing segment comprises a cEt sugar, cEt sugar, and 2O-methoxyethyl sugar in the 5 to 3 direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.

96. The compound of claim 95, wherein the modified oligonucleotide is SEQ ID NO: 440.

97. The compound of claim 95, wherein the modified oligonucleotide is SEQ ID NO: 455.

98. The compound of claim 95, wherein the modified oligonucleotide is SEQ ID NO: 598.

99. The compound of claim 95, wherein the compound consists of the modified oligonucleotide.

100. The compound of claim 95, wherein the modified oligonucleotide further comprises a conjugate group.

101. A composition comprising the compound of claim 95 or salt thereof and a pharmaceutically acceptable carrier.

102. A method of treating or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the compound of claim 95, thereby treating, preventing, or ameliorating the disease.

103. The method of claim 102, wherein the complement alternative pathway is activated greater than normal.

104. The method of claim 102, wherein the disease is macular degeneration.

105. The method of claim 104, wherein the macular degeneration is wet macular degeneration (AMD).

106. The method of claim 102, wherein the disease is a kidney disease.

Description

DETAILED DESCRIPTION

[0007] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of or means and/or unless stated otherwise. Furthermore, the use of the term including as well as other forms, such as includes and included, is not limiting. Also, terms such as element or component encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0008] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

[0009] Unless otherwise indicated, the following terms have the following meanings:

[0010] 2-O-methoxyethyl (also 2-MOE and 2-O(CH.sub.2).sub.2OCH.sub.3) refers to an O-methoxy-ethyl modification at the 2 position of a furanose ring. A 2-O-methoxyethyl modified sugar is a modified sugar.

[0011] 2-MOE nucleoside (also 2-O-methoxyethyl nucleoside) means a nucleoside comprising a 2-MOE modified sugar moiety.

[0012] 2-substituted nucleoside means a nucleoside comprising a substituent at the 2-position of the furanosyl ring other than H or OH. In certain embodiments, 2 substituted nucleosides include nucleosides with bicyclic sugar modifications.

[0013] 3 target site refers to the nucleotide of a target nucleic acid which is complementary to the 3-most nucleotide of a particular antisense compound.

[0014] 5 target site refers to the nucleotide of a target nucleic acid which is complementary to the 5-most nucleotide of a particular antisense compound.

[0015] 5-methylcytosine means a cytosine modified with a methyl group attached to the 5 position. A 5-methylcytosine is a modified nucleobase.

[0016] About means within +10% of a value. For example, if it is stated, the compounds affected at least about 70% inhibition of CFB, it is implied that CFB levels are inhibited within a range of 60% and 80%.

[0017] Administration or administering refers to routes of introducing an antisense compound provided herein to a subject to perform its intended function. An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

[0018] Amelioration refers to a lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art.

[0019] Animal refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

[0020] Antisense activity means any detectable or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid.

[0021] Antisense compound means an oligomeric compound that is is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

[0022] Antisense inhibition means reduction of target nucleic acid levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound.

[0023] Antisense mechanisms are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing.

[0024] Antisense oligonucleotide means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.

[0025] Base complementarity refers to the capacity for the precise base pairing of nucleobases of an antisense oligonucleotide with corresponding nucleobases in a target nucleic acid (i.e., hybridization), and is mediated by Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen binding between corresponding nucleobases.

[0026] Bicyclic sugar moiety means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2-carbon and the 4-carbon of the furanosyl.

[0027] Bicyclic nucleic acid or BNA or BNA nucleosides means nucleic acid monomers having a bridge connecting two carbon atoms between the 4 and 2 position of the nucleoside sugar unit, thereby forming a bicyclic sugar. Examples of such bicyclic sugar include, but are not limited to A) ?-L-Methyleneoxy (4-CH.sub.2O2) LNA, (B) ?-D-Methyleneoxy (4CH.sub.2O2) LNA, (C) Ethyleneoxy)(4(CH.sub.2).sub.2O?2? LNA, (D) Aminooxy (4CH.sub.2ON(R)2) LNA and (E) Oxyamino (4CH.sub.2N(R)O2) LNA, as depicted below.

##STR00001##

[0028] As used herein, LNA compounds include, but are not limited to, compounds having at least one bridge between the 4 and the 2 position of the sugar wherein each of the bridges independently comprises 1 or from 2 to 4 linked groups independently selected from [C(R.sub.1)(R.sub.2].sub.n, C(R.sub.1)?C(R.sub.2), C(R.sub.1)?N, C(?NR.sub.1), C(?O), C(?S), O, Si(R.sub.1).sub.2, S(?O).sub.x and N(R.sub.1); wherein: x is 0, 1, or 2; n is 1, 2, 3, or 4; each R.sub.1 and R.sub.2 is, independently, H, a protecting group, hydroxyl, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, a heterocycle radical, a substituted heterocycle radical, heteroaryl, substituted heteroaryl, C.sub.5-C.sub.7 alicyclic radical, substituted C.sub.5-C.sub.7 alicyclic radical, halogen, OJ.sub.1, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, COOJ.sub.1, acyl (C(?O)H), substituted acyl, CN, sulfonyl (S(?O).sub.2-J.sub.1), or sulfoxyl (S(?O)-J.sub.1); and each J.sub.1 and J.sub.2 is, independently, H, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, acyl (C(?O)H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C.sub.1-C.sub.12 aminoalkyl, substituted C.sub.1-C.sub.12 aminoalkyl or a protecting group.

[0029] Examples of 4-2 bridging groups encompassed within the definition of LNA include, but are not limited to one of formulae: [C(R.sub.1)(R.sub.2)].sub.n, [C(R.sub.1)(R.sub.2)].sub.nO, C(R.sub.1R.sub.2)N(R.sub.1)O or C(R.sub.1R.sub.2)ON(R.sub.1). Furthermore, other bridging groups encompassed with the definition of LNA are 4CH.sub.22, 4(CH.sub.2).sub.2-2, 4(CH.sub.2).sub.3-2, 4CH.sub.2O2, 4(CH.sub.2).sub.2O-2, 4CH.sub.2ON(R.sub.1)-2 and 4CH.sub.2N(R.sub.1)O- 2-bridges, wherein each R.sub.1 and R.sub.2 is, independently, H, a protecting group or C.sub.1-C.sub.12 alkyl.

[0030] Also included within the definition of LNA according to the invention are LNAs in which the 2-hydroxyl group of the ribosyl sugar ring is connected to the 4 carbon atom of the sugar ring, thereby forming a methyleneoxy (4CH.sub.2O2) bridge to form the bicyclic sugar moiety. The bridge can also be a methylene (CH.sub.2) group connecting the 2 oxygen atom and the 4 carbon atom, for which the term methyleneoxy (4CH.sub.2O-2) LNA is used. Furthermore; in the case of the bicylic sugar moiety having an ethylene bridging group in this position, the term ethyleneoxy (4CH.sub.2CH.sub.2O-2) LNA is used. ?-L-methyleneoxy (4CH.sub.2O2), an isomer of methyleneoxy (4CH.sub.2O-2) LNA is also encompassed within the definition of LNA, as used herein.

[0031] Cap structure or terminal cap moiety means chemical modifications, which have been incorporated at either terminus of an antisense compound.

[0032] cEt or constrained ethyl means a bicyclic sugar moiety comprising a bridge connecting the 4-carbon and the 2-carbon, wherein the bridge has the formula: 4CH(CH.sub.3)O-2.

[0033] Constrained ethyl nucleoside (also cEt nucleoside) means a nucleoside comprising a bicyclic sugar moiety comprising a 4CH(CH.sub.3)O-2 bridge.

[0034] Complement Factor B (CFB) means any nucleic acid or protein of CFB. CFB nucleic acid means any nucleic acid encoding CFB. For example, in certain embodiments, a CFB nucleic acid includes a DNA sequence encoding CFB, an RNA sequence transcribed from DNA encoding CFB (including genomic DNA comprising introns and exons), including a non-protein encoding (i.e. non-coding) RNA sequence, and an mRNA sequence encoding CFB. CFB mRNA means an mRNA encoding a CFB protein.

[0035] CFB specific inhibitor refers to any agent capable of specifically inhibiting CFB RNA and/or CFB protein expression or activity at the molecular level. For example, CFB specific inhibitors include nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of CFB RNA and/or CFB protein.

[0036] Chemically distinct region refers to a region of an antisense compound that is in some way chemically different than another region of the same antisense compound. For example, a region having 2O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2O-methoxyethyl modifications.

[0037] Chimeric antisense compounds means antisense compounds that have at least 2 chemically distinct regions, each position having a plurality of subunits.

[0038] Complementarity means the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid.

[0039] Comprise, comprises and comprising will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

[0040] Contiguous nucleobases means nucleobases immediately adjacent to each other.

[0041] Deoxyribonucleotide means a nucleotide having a hydrogen at the 2 position of the sugar portion of the nucleotide. Deoxyribonucleotides may be modified with any of a variety of substituents.

[0042] Designing or Designed to refer to the process of designing an oligomeric compound that specifically hybridizes with a selected nucleic acid molecule.

[0043] Effective amount means the amount of active pharmaceutical agent sufficient to effectuate a desired physiological outcome in an individual in need of the agent. The effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual's medical condition, and other relevant factors.

[0044] Efficacy means the ability to produce a desired effect.

[0045] Expression includes all the functions by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to the products of transcription and translation.

[0046] Fully complementary or 100% complementary means each nucleobase of a first nucleic acid has a complementary nucleobase in a second nucleic acid. In certain embodiments, a first nucleic acid is an antisense compound and a target nucleic acid is a second nucleic acid.

[0047] Gapmer means a chimeric antisense compound in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the gap and the external regions may be referred to as the wings.

[0048] Hybridization means the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense oligonucleotide and a nucleic acid target.

[0049] Identifying an animal having, or at risk for having, a disease, disorder and/or condition means identifying an animal having been diagnosed with the disease, disorder and/or condition or identifying an animal predisposed to develop the disease, disorder and/or condition. Such identification may be accomplished by any method including evaluating an individual's medical history and standard clinical tests or assessments.

[0050] Immediately adjacent means there are no intervening elements between the immediately adjacent elements.

[0051] Individual means a human or non-human animal selected for treatment or therapy.

[0052] Inhibiting the expression or activity refers to a reduction, blockade of the expression or activity and does not necessarily indicate a total elimination of expression or activity.

[0053] Internucleoside linkage refers to the chemical bond between nucleosides.

[0054] Lengthened antisense oligonucleotides are those that have one or more additional nucleosides relative to an antisense oligonucleotide disclosed herein.

[0055] Linked deoxynucleoside means a nucleic acid base (A, G, C, T, U) substituted by deoxyribose linked by a phosphate ester to form a nucleotide.

[0056] Linked nucleosides means adjacent nucleosides linked together by an internucleoside linkage.

[0057] Mismatch or non-complementary nucleobase refers to the case when a nucleobase of a first nucleic acid is not capable of pairing with the corresponding nucleobase of a second or target nucleic acid.

[0058] Modified internucleoside linkage refers to a substitution or any change from a naturally occurring internucleoside bond (i.e. a phosphodiester internucleoside bond).

[0059] Modified nucleobase means any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil. An unmodified nucleobase means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).

[0060] Modified nucleoside means a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase.

[0061] Modified nucleotide means a nucleotide having, independently, a modified sugar moiety, modified internucleoside linkage, or modified nucleobase.

[0062] Modified oligonucleotide means an oligonucleotide comprising at least one modified internucleoside linkage, a modified sugar, and/or a modified nucleobase.

[0063] Modified sugar means substitution and/or any change from a natural sugar moiety.

[0064] Modulating refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating CFB mRNA can mean to increase or decrease the level of CFB mRNA and/or CFB protein in a cell, tissue, organ or organism. A modulator effects the change in the cell, tissue, organ or organism. For example, a CFB antisense compound can be a modulator that decreases the amount of CFB mRNA and/or CFB protein in a cell, tissue, organ or organism.

[0065] Monomer refers to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides, whether naturally occurring or modified.

[0066] Motif means the pattern of unmodified and modified nucleosides in an antisense compound.

[0067] Natural sugar moiety means a sugar moiety found in DNA (2H) or RNA (2OH).

[0068] Naturally occurring internucleoside linkage means a 3 to 5 phosphodiester linkage.

[0069] Non-complementary nucleobase refers to a pair of nucleobases that do not form hydrogen bonds with one another or otherwise support hybridization.

[0070] Nucleic acid refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0071] Nucleobase means a heterocyclic moiety capable of pairing with a base of another nucleic acid.

[0072] Nucleobase complementarity refers to a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleobase refers to a nucleobase of an antisense compound that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of an antisense compound is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair.

[0073] Nucleobase sequence means the order of contiguous nucleobases independent of any sugar, linkage, and/or nucleobase modification.

[0074] Nucleoside means a nucleobase linked to a sugar.

[0075] Nucleoside mimetic includes those structures used to replace the sugar or the sugar and the base and not necessarily the linkage at one or more positions of an oligomeric compound such as for example nucleoside mimetics having morpholino, cyclohexenyl, cyclohexyl, tetrahydropyranyl, bicyclo or tricyclo sugar mimetics, e.g., non furanose sugar units. Nucleotide mimetic includes those structures used to replace the nucleoside and the linkage at one or more positions of an oligomeric compound such as for example peptide nucleic acids or morpholinos (morpholinos linked by N(H)C(?O)O or other non-phosphodiester linkage). Sugar surrogate overlaps with the slightly broader term nucleoside mimetic but is intended to indicate replacement of the sugar unit (furanose ring) only. The tetrahydropyranyl rings provided herein are illustrative of an example of a sugar surrogate wherein the furanose sugar group has been replaced with a tetrahydropyranyl ring system. Mimetic refers to groups that are substituted for a sugar, a nucleobase, and/or internucleoside linkage. Generally, a mimetic is used in place of the sugar or sugar-internucleoside linkage combination, and the nucleobase is maintained for hybridization to a selected target.

[0076] Nucleotide means a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside.

[0077] Oligomeric compound means a polymer of linked monomeric subunits which is capable of hybridizing to at least a region of a nucleic acid molecule.

[0078] Oligonucleoside means an oligonucleotide in which the internucleoside linkages do not contain a phosphorus atom.

[0079] Oligonucleotide means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another.

[0080] Parenteral administration means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

[0081] Pharmaceutical composition means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition may comprise one or more active pharmaceutical agents and a sterile aqueous solution.

[0082] Pharmaceutically acceptable salts means physiologically and pharmaceutically acceptable salts of antisense compounds, i.e., salts that retain the desired biological activity of the parent oligonucleotide and do not impart undesired toxicological effects thereto.

[0083] Phosphorothioate linkage means a linkage between nucleosides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage is a modified internucleoside linkage.

[0084] Portion means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an antisense compound

[0085] Prevent refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time from minutes to indefinitely. Prevent also means reducing the risk of developing a disease, disorder, or condition.

[0086] Prophylactically effective amount refers to an amount of a pharmaceutical agent that provides a prophylactic or preventative benefit to an animal.

[0087] Region is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic.

[0088] Ribonucleotide means a nucleotide having a hydroxy at the 2 position of the sugar portion of the nucleotide. Ribonucleotides may be modified with any of a variety of substituents.

[0089] Segments are defined as smaller or sub-portions of regions within a target nucleic acid.

[0090] Side effects means physiological disease and/or conditions attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality.

[0091] Sites, as used herein, are defined as unique nucleobase positions within a target nucleic acid.

[0092] Slows progression means decrease in the development of the said disease.

[0093] Specifically hybridizable refers to an antisense compound having a sufficient degree of complementarity between an antisense oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays and therapeutic treatments. Stringent hybridization conditions or stringent conditions refer to conditions under which an oligomeric compound will hybridize to its target sequence, but to a minimal number of other sequences.

[0094] Subject means a human or non-human animal selected for treatment or therapy.

[0095] Target refers to a protein, the modulation of which is desired.

[0096] Target gene refers to a gene encoding a target.

[0097] Targeting means the process of design and selection of an antisense compound that will specifically hybridize to a target nucleic acid and induce a desired effect.

[0098] Target nucleic acid, target RNA, target RNA transcript and nucleic acid target all mean a nucleic acid capable of being targeted by antisense compounds.

[0099] Target region means a portion of a target nucleic acid to which one or more antisense compounds is targeted.

[0100] Target segment means the sequence of nucleotides of a target nucleic acid to which an antisense compound is targeted. 5 target site refers to the 5-most nucleotide of a target segment. 3 target site refers to the 3-most nucleotide of a target segment.

[0101] Therapeutically effective amount means an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual.

[0102] Treat refers to administering a pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal. In certain embodiments, one or more pharmaceutical compositions can be administered to the animal.

[0103] Unmodified nucleobases mean the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).

[0104] Unmodified nucleotide means a nucleotide composed of naturally occurring nucleobases, sugar moieties, and internucleoside linkages. In certain embodiments, an unmodified nucleotide is an RNA nucleotide (i.e. ?-D-ribonucleosides) or a DNA nucleotide (i.e. ?-D-deoxyribonucleoside).

Certain Embodiments

[0105] Certain embodiments provide methods, compounds and compositions for inhibiting Complement Factor B (CFB) expression.

[0106] Certain embodiments provide antisense compounds targeted to a CFB nucleic acid. In certain embodiments, the CFB nucleic acid has the sequence set forth in GENBANK Accession No. NM_001710.5 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No NW_001116486.1 truncated from nucleotides 536000 to 545000 (incorporated herein as SEQ ID NO: 3), GENBANK Accession No. XM_001113553.2 (incorporated herein as SEQ ID NO: 4), or GENBANK Accession No. NM 008198.2 (incorporated herein as SEQ ID NO: 5).

[0107] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808.

[0108] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 9 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808.

[0109] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808.

[0110] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 11 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808.

[0111] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808.

[0112] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 6-808.

[0113] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 6-808.

[0114] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleobases 30-49, 48-63, 150-169, 151-170, 152-171, 154-169, 154-173, 156-171, 156-175, 157-176, 158-173, 158-177, 480-499, 600-619, 638-657, 644-663, 738-757, 1089-1108, 1135-1154, 1141-1160, 1147-1166, 1150-1169, 1153-1172, 1159-1178, 1162-1181, 1165-1184, 1171-1186, 1171-1190, 1173-1188, 1173-1192, 1175-1190, 1175-1194, 1177-1196, 1183-1202, 1208-1227, 1235-1254, 1298-1317, 1304-1323, 1310-1329, 1316-1335, 1319-1338, 1322-1341, 1328-1347, 1349-1368, 1355-1374, 1393-1412, 1396-1415, 1399-1418, 1405-1424, 1421-1440, 1621-1640, 1646-1665, 1646-1665, 1647-1666, 1689-1708, 1749-1768, 1763-1782, 1912-1931, 2073-2092, 2085-2104, 2166-2185, 2172-2191, 2189-2208, 2191-2210, 2193-2212, 2195-2210, 2195-2214, 2196-2215, 2197-2212, 2197-2216, 2202-2221, 2223-2238, 2223-2242, 2225-2240, 2226-2245, 2227-2242, 2227-2246, 2238-2257, 2241-2260, 2267-2286, 2361-2380, 2388-2407, 2397-2416, 2448-2467, 2453-2472, 2455-2474, 2457-2472, 2457-2476, 2459-2474, 2459-2478, 2461-2476, 2461-2480, 2532-2551, 2550-2569, 2551-2566, 2551-2570, 2552-2568, 2552-2570, 2552-2571, 2553-2568, 2553-2570, 2553-2571, 2553-2572, 2554-2571, 2554-2572, 2554-2573, 2555-2570, 2555-2572, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2573, 2557-2574, 2557-2575, 2557-2576, 2558-2575, 2558-2576, 2558-2577, 2559-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2576, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2578, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2566-2585, 2567-2582, 2567-2584, 2567-2586, 2568-2583, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2585, 2570-2587, 2570-2589, 2571-2586, 2571-2588, 2571-2590, 2572-2589, 2572-2590, 2572-2591, 2573-2590, 2573-2592, 2574-2590, 2574-2591, 2574-2593, 2575-2590, 2575-2591, 2575-2592, 2575-2594, 2576-2593, 2576-2595, 2577-2594, 2577-2595, 2577-2596, 2578-2594, 2578-2596, 2578-2597, 2579-2598, 2580-2596, 2580-2597, 2580-2598, 2580-2599, 2581-2597, 2581-2598, 2581-2599, 2581-2600, 2582-2598, 2582-2599, 2582-2600, 2582-2601, 2583-2599, 2583-2600, 2583-2601, 2583-2602, 2584-2600, 2584-2601, 2584-2602, 2584-2603, 2585-2601, 2585-2603, 2585-2604, 2586-2601, 2586-2602, 2586-2604, 2586-2605, 2587-2602, 2587-2603, 2587-2605, 2587-2606, 2588-2603, 2588-2604, 2588-2605, 2588-2606, 2588-2607, 2589-2604, 2589-2605, 2589-2606, 2589-2607, 2589-2608, 2590-2605, 2590-2606, 2590-2607, 2590-2608, 2590-2609, 2590-2609, 2591-2607, 2591-2608, 2591-2609, 2591-2610, 2592-2607, 2592-2608, 2592-2609, 2592-2610, 2592-2611, 2593-2608, 2593-2609, 2593-2610, 2593-2612, 2594-2609, 2594-2610, 2594-2611, 2594-2612, 2594-2613, 2595-2610, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2596-2611, 2596-2612, 2596-2613, 2596-2614, 2596-2615, 2597-2612, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2602-2617, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2603-2618, 2603-2619, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2626, 2608-2627, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2611-2626, 2611-2627, 2611-2628, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2631, or 2616-2631 of SEQ ID NO: 1, wherein said modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 1.

[0115] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 30-49, 48-63, 150-169, 151-170, 152-171, 154-169, 154-173, 156-171, 156-175, 157-176, 158-173, 158-177, 480-499, 600-619, 638-657, 644-663, 738-757, 1089-1108, 1135-1154, 1141-1160, 1147-1166, 1150-1169, 1153-1172, 1159-1178, 1162-1181, 1165-1184, 1171-1186, 1171-1190, 1173-1188, 1173-1192, 1175-1190, 1175-1194, 1177-1196, 1183-1202, 1208-1227, 1235-1254, 1298-1317, 1304-1323, 1310-1329, 1316-1335, 1319-1338, 1322-1341, 1328-1347, 1349-1368, 1355-1374, 1393-1412, 1396-1415, 1399-1418, 1405-1424, 1421-1440, 1621-1640, 1646-1665, 1646-1665, 1647-1666, 1689-1708, 1749-1768, 1763-1782, 1912-1931, 2073-2092, 2085-2104, 2166-2185, 2172-2191, 2189-2208, 2191-2210, 2193-2212, 2195-2210, 2195-2214, 2196-2215, 2197-2212, 2197-2216, 2202-2221, 2223-2238, 2223-2242, 2225-2240, 2226-2245, 2227-2242, 2227-2246, 2238-2257, 2241-2260, 2267-2286, 2361-2380, 2388-2407, 2397-2416, 2448-2467, 2453-2472, 2455-2474, 2457-2472, 2457-2476, 2459-2474, 2459-2478, 2461-2476, 2461-2480, 2532-2551, 2550-2569, 2551-2566, 2551-2570, 2552-2568, 2552-2570, 2552-2571, 2553-2568, 2553-2570, 2553-2571, 2553-2572, 2554-2571, 2554-2572, 2554-2573, 2555-2570, 2555-2572, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2573, 2557-2574, 2557-2575, 2557-2576, 2558-2575, 2558-2576, 2558-2577, 2559-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2576, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2578, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2566-2585, 2567-2582, 2567-2584, 2567-2586, 2568-2583, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2585, 2570-2587, 2570-2589, 2571-2586, 2571-2588, 2571-2590, 2572-2589, 2572-2590, 2572-2591, 2573-2590, 2573-2592, 2574-2590, 2574-2591, 2574-2593, 2575-2590, 2575-2591, 2575-2592, 2575-2594, 2576-2593, 2576-2595, 2577-2594, 2577-2595, 2577-2596, 2578-2594, 2578-2596, 2578-2597, 2579-2598, 2580-2596, 2580-2597, 2580-2598, 2580-2599, 2581-2597, 2581-2598, 2581-2599, 2581-2600, 2582-2598, 2582-2599, 2582-2600, 2582-2601, 2583-2599, 2583-2600, 2583-2601, 2583-2602, 2584-2600, 2584-2601, 2584-2602, 2584-2603, 2585-2601, 2585-2603, 2585-2604, 2586-2601, 2586-2602, 2586-2604, 2586-2605, 2587-2602, 2587-2603, 2587-2605, 2587-2606, 2588-2603, 2588-2604, 2588-2605, 2588-2606, 2588-2607, 2589-2604, 2589-2605, 2589-2606, 2589-2607, 2589-2608, 2590-2605, 2590-2606, 2590-2607, 2590-2608, 2590-2609, 2590-2609, 2591-2607, 2591-2608, 2591-2609, 2591-2610, 2592-2607, 2592-2608, 2592-2609, 2592-2610, 2592-2611, 2593-2608, 2593-2609, 2593-2610, 2593-2612, 2594-2609, 2594-2610, 2594-2611, 2594-2612, 2594-2613, 2595-2610, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2596-2611, 2596-2612, 2596-2613, 2596-2614, 2596-2615, 2597-2612, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2602-2617, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2603-2618, 2603-2619, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2626, 2608-2627, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2611-2626, 2611-2627, 2611-2628, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2631, or 2616-2631 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 1.

[0116] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleobases 1608-1627, 1685-1704, 1686-1705, 1751-1770, 1769-1784, 1871-1890, 1872-1891, 1873-1892, 1875-1890, 1875-1894, 1877-1892, 1877-1896, 1878-1897, 1879-1894, 1879-1898, 2288-2307, 2808-2827, 2846-2865, 2852-2871, 2946-2965, 3773-3792, 3819-3838, 3825-3844, 3831-3850, 3834-3853, 3837-3856, 3843-3862, 4151-4166, 4151-4170, 4153-4172, 4159-4178, 4184-4203, 4211-4230, 4609-4628, 4612-4631, 4615-4634, 4621-4640, 4642-4661, 4648-4667, 4686-4705, 4689-4708, 4692-4711, 4698-4717, 4714-4733, 5270-5289, 5295-5314, 5296-5315, 5830-5849, 5890-5909, 5904-5923, 6406-6425, 6662-6681, 6674-6693, 6954-6973, 6960-6979, 6977-6996, 6979-6998, 6981-7000, 6983-6998, 6983-7002, 6984-7003, 6985-7000, 6985-7004, 6990-7009, 7122-7141, 7125-7144, 7151-7170, 7353-7372, 7362-7381, 7683-7702, 7688-7707, 7690-7709, 7692-7707, 7692-7711, 7694-7709, 7694-7713, 7696-7711, 7696-7715, 7767-7786, 7785-7804, 7786-7801, 7787-7803, 7787-7805, 7787-7806, 7788-7803, 7788-7805, 7788-7806, 7788-7807, 7789-7806, 7789-7807, 7789-7808, 7790-7805, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7808, 7792-7809, 7792-7810, 7792-7811, 7793-7810, 7793-7811, 7793-7812, 7794-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7811, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7813, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7801-7820, 7802-7817, 7802-7819, 7802-7821, 7803-7818, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7820, 7805-7822, 7805-7824, 7806-7821, 7806-7823, 7806-7825, 7807-7824, 7807-7825, 7807-7826, 7808-7825, 7808-7827, 7809-7825, 7809-7826, 7809-7828, 7810-7825, 7810-7826, 7810-7827, 7810-7829, 7811-7828, 7811-7830, 7812-7829, 7812-7830, 7812-7831, 7813-7829, 7813-7831, 7813-7832, 7814-7833, 7815-7831, 7815-7832, 7815-7833, 7815-7834, 7816-7832, 7816-7833, 7816-7834, 7816-7835, 7817-7833, 7817-7834, 7817-7835, 7817-7836, 7818-7834, 7818-7835, 7818-7836, 7818-7837, 7819-7835, 7819-7836, 7819-7837, 7819-7838, 7820-7836, 7820-7838, 7820-7839, 7821-7836, 7821-7837, 7821-7839, 7821-7840, 7822-7837, 7822-7838, 7822-7840, 7822-7841, 7823-7838, 7823-7839, 7823-7839, 7823-7840, 7823-7841, 7823-7842, 7824-7839, 7824-7840, 7824-7840, 7824-7841, 7824-7842, 7824-7843, 7825-7840, 7825-7841, 7825-7842, 7825-7843, 7825-7844, 7826-7842, 7826-7843, 7826-7844, 7826-7845, 7827-7842, 7827-7843, 7827-7844, 7827-7845, 7827-7846, 7828-7843, 7828-7844, 7828-7845, 7828-7847, 7829-7844, 7829-7845, 7829-7846, 7829-7847, 7829-7848, 7830-7845, 7830-7846, 7830-7847, 7830-7848, 7830-7849, 7831-7846, 7831-7847, 7831-7848, 7831-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7850, 7834-7851, 7834-7852, 7834-7853, 7835-7850, 7835-7851, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7853, 7836-7854, 7836-7855, 7837-7852, 7837-7853, 7837-7854, 7837-7855, 7837-7856, 7838-7853, 7838-7854, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7861, 7843-7862, 7844-7859, 7844-7860, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7845-7862, 7846-7861, or 7846-7862 of SEQ ID NO: 2, wherein said modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 2.

[0117] Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 1608-1627, 1685-1704, 1686-1705, 1751-1770, 1769-1784, 1871-1890, 1872-1891, 1873-1892, 1875-1890, 1875-1894, 1877-1892, 1877-1896, 1878-1897, 1879-1894, 1879-1898, 2288-2307, 2808-2827, 2846-2865, 2852-2871, 2946-2965, 3773-3792, 3819-3838. 3825-3844, 3831-3850, 3834-3853, 3837-3856, 3843-3862, 4151-4166, 4151-4170, 4153-4172, 4159-4178, 4184-4203, 4211-4230, 4609-4628, 4612-4631, 4615-4634, 4621-4640, 4642-4661, 4648-4667, 4686-4705, 4689-4708, 4692-4711, 4698-4717, 4714-4733, 5270-5289, 5295-5314, 5296-5315, 5830-5849, 5890-5909, 5904-5923, 6406-6425, 6662-6681, 6674-6693, 6954-6973, 6960-6979, 6977-6996, 6979-6998, 6981-7000, 6983-6998, 6983-7002, 6984-7003, 6985-7000, 6985-7004, 6990-7009, 7122-7141, 7125-7144, 7151-7170, 7353-7372, 7362-7381, 7683-7702, 7688-7707, 7690-7709, 7692-7707, 7692-7711, 7694-7709, 7694-7713, 7696-7711, 7696-7715, 7767-7786, 7785-7804, 7786-7801, 7787-7803, 7787-7805, 7787-7806, 7788-7803, 7788-7805, 7788-7806, 7788-7807, 7789-7806, 7789-7807, 7789-7808, 7790-7805, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7808, 7792-7809, 7792-7810, 7792-7811, 7793-7810, 7793-7811, 7793-7812, 7794-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7811, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7813, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7801-7820, 7802-7817, 7802-7819, 7802-7821, 7803-7818, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7820, 7805-7822, 7805-7824, 7806-7821, 7806-7823, 7806-7825, 7807-7824, 7807-7825, 7807-7826, 7808-7825, 7808-7827, 7809-7825, 7809-7826, 7809-7828, 7810-7825, 7810-7826, 7810-7827, 7810-7829, 7811-7828, 7811-7830, 7812-7829, 7812-7830, 7812-7831, 7813-7829, 7813-7831, 7813-7832, 7814-7833, 7815-7831, 7815-7832, 7815-7833, 7815-7834, 7816-7832, 7816-7833, 7816-7834, 7816-7835, 7817-7833, 7817-7834, 7817-7835, 7817-7836, 7818-7834, 7818-7835, 7818-7836, 7818-7837, 7819-7835, 7819-7836, 7819-7837, 7819-7838, 7820-7836, 7820-7838, 7820-7839, 7821-7836, 7821-7837, 7821-7839, 7821-7840, 7822-7837, 7822-7838, 7822-7840, 7822-7841, 7823-7838, 7823-7839, 7823-7839, 7823-7840, 7823-7841, 7823-7842, 7824-7839, 7824-7840, 7824-7840, 7824-7841, 7824-7842, 7824-7843, 7825-7840, 7825-7841, 7825-7842, 7825-7843, 7825-7844, 7826-7842, 7826-7843, 7826-7844, 7826-7845, 7827-7842, 7827-7843, 7827-7844, 7827-7845, 7827-7846, 7828-7843, 7828-7844, 7828-7845, 7828-7847, 7829-7844, 7829-7845, 7829-7846, 7829-7847, 7829-7848, 7830-7845, 7830-7846, 7830-7847, 7830-7848, 7830-7849, 7831-7846, 7831-7847, 7831-7848, 7831-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7850, 7834-7851, 7834-7852, 7834-7853, 7835-7850, 7835-7851, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7853, 7836-7854, 7836-7855, 7837-7852, 7837-7853, 7837-7854, 7837-7855, 7837-7856, 7838-7853, 7838-7854, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7861, 7843-7862, 7844-7859, 7844-7860, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7845-7862, 7846-7861, and 7846-7862 of SEQ ID NO: 2, wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 2.

[0118] In certain embodiments, antisense compounds or oligonucleotides target a region of a CFB nucleic acid. In certain embodiments, such compounds or oligonucleotides targeted to a region of a CFB nucleic acid have a contiguous nucleobase portion that is complementary to an equal length nucleobase portion of the region. For example, the portion can be at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion of a region recited herein. In certain embodiments, such compounds or oligonucleotide target the following nucleotide regions of SEQ ID NO: 1: 30-49, 48-63, 150-169, 151-170, 152-171, 154-169, 154-173, 156-171, 156-175, 157-176, 158-173, 158-177, 480-499, 600-619, 638-657, 644-663, 738-757, 1089-1108, 1135-1154, 1141-1160, 1147-1166, 1150-1169, 1153-1172, 1159-1178, 1162-1181, 1165-1184, 1171-1186, 1171-1190, 1173-1188, 1173-1192, 1175-1190, 1175-1194, 1177-1196, 1183-1202, 1208-1227, 1235-1254, 1298-1317, 1304-1323, 1310-1329, 1316-1335, 1319-1338, 1322-1341, 1328-1347, 1349-1368, 1355-1374, 1393-1412, 1396-1415, 1399-1418, 1405-1424, 1421-1440, 1621-1640, 1646-1665, 1646-1665, 1647-1666, 1689-1708, 1749-1768, 1763-1782, 1912-1931, 2073-2092, 2085-2104, 2166-2185, 2172-2191, 2189-2208, 2191-2210, 2193-2212, 2195-2210, 2195-2214, 2196-2215, 2197-2212, 2197-2216, 2202-2221, 2223-2238, 2223-2242, 2225-2240, 2226-2245, 2227-2242, 2227-2246, 2238-2257, 2241-2260, 2267-2286, 2361-2380, 2388-2407, 2397-2416, 2448-2467, 2453-2472, 2455-2474, 2457-2472, 2457-2476, 2459-2474, 2459-2478, 2461-2476, 2461-2480, 2532-2551, 2550-2569, 2551-2566, 2551-2570, 2552-2568, 2552-2570, 2552-2571, 2553-2568, 2553-2570, 2553-2571, 2553-2572, 2554-2571, 2554-2572, 2554-2573, 2555-2570, 2555-2572, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2573, 2557-2574, 2557-2575, 2557-2576, 2558-2575, 2558-2576, 2558-2577, 2559-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2576, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2578, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2566-2585, 2567-2582, 2567-2584, 2567-2586, 2568-2583, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2585, 2570-2587, 2570-2589, 2571-2586, 2571-2588, 2571-2590, 2572-2589, 2572-2590, 2572-2591, 2573-2590, 2573-2592, 2574-2590, 2574-2591, 2574-2593, 2575-2590, 2575-2591, 2575-2592, 2575-2594, 2576-2593, 2576-2595, 2577-2594, 2577-2595, 2577-2596, 2578-2594, 2578-2596, 2578-2597, 2579-2598, 2580-2596, 2580-2597, 2580-2598, 2580-2599, 2581-2597, 2581-2598, 2581-2599, 2581-2600, 2582-2598, 2582-2599, 2582-2600, 2582-2601, 2583-2599, 2583-2600, 2583-2601, 2583-2602, 2584-2600, 2584-2601, 2584-2602, 2584-2603, 2585-2601, 2585-2603, 2585-2604, 2586-2601, 2586-2602, 2586-2604, 2586-2605, 2587-2602, 2587-2603, 2587-2605, 2587-2606, 2588-2603, 2588-2604, 2588-2605, 2588-2606, 2588-2607, 2589-2604, 2589-2605, 2589-2606, 2589-2607, 2589-2608, 2590-2605, 2590-2606, 2590-2607, 2590-2608, 2590-2609, 2590-2609, 2591-2607, 2591-2608, 2591-2609, 2591-2610, 2592-2607, 2592-2608, 2592-2609, 2592-2610, 2592-2611, 2593-2608, 2593-2609, 2593-2610, 2593-2612, 2594-2609, 2594-2610, 2594-2611, 2594-2612, 2594-2613, 2595-2610, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2596-2611, 2596-2612, 2596-2613, 2596-2614, 2596-2615, 2597-2612, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2602-2617, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2603-2618, 2603-2619, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2626, 2608-2627, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2611-2626, 2611-2627, 2611-2628, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2631, and 2616-2631.

[0119] In certain embodiments, antisense compounds or oligonucleotides target a region of a CFB nucleic acid. In certain embodiments, such compounds or oligonucleotides targeted to a region of a CFB nucleic acid have a contiguous nucleobase portion that is complementary to an equal length nucleobase portion of the region. For example, the portion can be at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion of a region recited herein. In certain embodiments, such compounds or oligonucleotide target the following nucleotide regions of SEQ ID NO: 2: 1608-1627, 1685-1704, 1686-1705, 1751-1770, 1769-1784, 1871-1890, 1872-1891, 1873-1892, 1875-1890, 1875-1894, 1877-1892, 1877-1896, 1878-1897, 1879-1894, 1879-1898, 2288-2307, 2808-2827, 2846-2865, 2852-2871, 2946-2965, 3773-3792, 3819-3838, 3825-3844, 3831-3850, 3834-3853, 3837-3856, 3843-3862, 4151-4166, 4151-4170, 4153-4172, 4159-4178, 4184-4203, 4211-4230, 4609-4628, 4612-4631, 4615-4634, 4621-4640, 4642-4661, 4648-4667, 4686-4705, 4689-4708, 4692-4711, 4698-4717, 4714-4733, 5270-5289, 5295-5314, 5296-5315, 5830-5849, 5890-5909, 5904-5923, 6406-6425, 6662-6681, 6674-6693, 6954-6973, 6960-6979, 6977-6996, 6979-6998, 6981-7000, 6983-6998, 6983-7002, 6984-7003, 6985-7000, 6985-7004, 6990-7009, 7122-7141, 7125-7144, 7151-7170, 7353-7372, 7362-7381, 7683-7702, 7688-7707, 7690-7709, 7692-7707, 7692-7711, 7694-7709, 7694-7713, 7696-7711, 7696-7715, 7767-7786, 7785-7804, 7786-7801, 7787-7803, 7787-7805, 7787-7806, 7788-7803, 7788-7805, 7788-7806, 7788-7807, 7789-7806, 7789-7807, 7789-7808, 7790-7805, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7808, 7792-7809, 7792-7810, 7792-7811, 7793-7810, 7793-7811, 7793-7812, 7794-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7811, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7813, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7801-7820, 7802-7817, 7802-7819, 7802-7821, 7803-7818, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7820, 7805-7822, 7805-7824, 7806-7821, 7806-7823, 7806-7825, 7807-7824, 7807-7825, 7807-7826, 7808-7825, 7808-7827, 7809-7825, 7809-7826, 7809-7828, 7810-7825, 7810-7826, 7810-7827, 7810-7829, 7811-7828, 7811-7830, 7812-7829, 7812-7830, 7812-7831, 7813-7829, 7813-7831, 7813-7832, 7814-7833, 7815-7831, 7815-7832, 7815-7833, 7815-7834, 7816-7832, 7816-7833, 7816-7834, 7816-7835, 7817-7833, 7817-7834, 7817-7835, 7817-7836, 7818-7834, 7818-7835, 7818-7836, 7818-7837, 7819-7835, 7819-7836, 7819-7837, 7819-7838, 7820-7836, 7820-7838, 7820-7839, 7821-7836, 7821-7837, 7821-7839, 7821-7840, 7822-7837, 7822-7838, 7822-7840, 7822-7841, 7823-7838, 7823-7839, 7823-7839, 7823-7840, 7823-7841, 7823-7842, 7824-7839, 7824-7840, 7824-7840, 7824-7841, 7824-7842, 7824-7843, 7825-7840, 7825-7841, 7825-7842, 7825-7843, 7825-7844, 7826-7842, 7826-7843, 7826-7844, 7826-7845, 7827-7842, 7827-7843, 7827-7844, 7827-7845, 7827-7846, 7828-7843, 7828-7844, 7828-7845, 7828-7847, 7829-7844, 7829-7845, 7829-7846, 7829-7847, 7829-7848, 7830-7845, 7830-7846, 7830-7847, 7830-7848, 7830-7849, 7831-7846, 7831-7847, 7831-7848, 7831-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7850, 7834-7851, 7834-7852, 7834-7853, 7835-7850, 7835-7851, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7853, 7836-7854, 7836-7855, 7837-7852, 7837-7853, 7837-7854, 7837-7855, 7837-7856, 7838-7853, 7838-7854, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7861, 7843-7862, 7844-7859, 7844-7860, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7845-7862, 7846-7861, and 7846-7862.

[0120] In certain embodiments, antisense compounds or oligonucleotides target the 3UTR of a CFB nucleic acid. In certain embodiments, antisense compounds or oligonucleotides target within nucleotides 2574-2626 of a CFB nucleic acid having the nucleobase sequence of SEQ ID NO: 1. In certain embodiments, antisense compounds or oligonucleotides have at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleotides 2574-2626 of a CFB nucleic acid having the nucleobase sequence of SEQ ID NO: 1.

[0121] In certain embodiments, antisense compounds or oligonucleotides target a region of a CFB nucleic acid having the nucleobase sequence of SEQ ID NO: 1 within nucleobases 2457-2631, 2457-2472, 2457-2474, 2457-2476, 2457-2566, 2457-2570, 2457-2571, 2457-2572, 2457-2573, 2457-2574, 2457-2575, 2457-2576, 2457-2577, 2457-2578, 2457-2579, 2457-2580, 2457-2581, 2457-2582, 2457-2583, 2457-2584, 2457-2585, 2457-2586, 2457-2587, 2457-2588, 2457-2589, 2457-2590, 2457-2591, 2457-2592, 2457-2593, 2457-2594, 2457-2595, 2457-2596, 2457-2597, 2457-2598, 2457-2599, 2457-2600, 2457-2601, 2457-2602, 2457-2603, 2457-2604, 2457-2605, 2457-2606, 2457-2607, 2457-2608, 2457-2609, 2457-2610, 2457-2611, 2457-2612, 2457-2613, 2457-2614, 2457-2615, 2457-2616, 2457-2617, 2457-2618, 2457-2619, 2457-2620, 2457-2621, 2457-2622, 2457-2623, 2457-2624, 2457-2625, 2457-2626, 2457-2627, 2457-2628, 2457-2629, 2457-2630, 2457-2631, 2459-2474, 2459-2476, 2459-2566, 2459-2570, 2459-2571, 2459-2572, 2459-2573, 2459-2574, 2459-2575, 2459-2576, 2459-2577, 2459-2578, 2459-2579, 2459-2580, 2459-2581, 2459-2582, 2459-2583, 2459-2584, 2459-2585, 2459-2586, 2459-2587, 2459-2588, 2459-2589, 2459-2590, 2459-2591, 2459-2592, 2459-2593, 2459-2594, 2459-2595, 2459-2596, 2459-2597, 2459-2598, 2459-2599, 2459-2600, 2459-2601, 2459-2602, 2459-2603, 2459-2604, 2459-2605, 2459-2606, 2459-2607, 2459-2608, 2459-2609, 2459-2610, 2459-2611, 2459-2612, 2459-2613, 2459-2614, 2459-2615, 2459-2616, 2459-2617, 2459-2618, 2459-2619. 2459-2620, 2459-2621, 2459-2622, 2459-2623, 2459-2624, 2459-2625, 2459-2626, 2459-2627, 2459-2628, 2459-2629, 2459-2630, 2459-2631, 2461-2476, 2461-2566, 2461-2570, 2461-2571, 2461-2572, 2461-2573, 2461-2574, 2461-2575, 2461-2576, 2461-2577, 2461-2578, 2461-2579, 2461-2580, 2461-2581, 2461-2582, 2461-2583, 2461-2584, 2461-2585, 2461-2586, 2461-2587, 2461-2588, 2461-2589, 2461-2590, 2461-2591, 2461-2592, 2461-2593, 2461-2594, 2461-2595, 2461-2596, 2461-2597, 2461-2598, 2461-2599, 2461-2600, 2461-2601, 2461-2602, 2461-2603, 2461-2604, 2461-2605, 2461-2606, 2461-2607, 2461-2608, 2461-2609, 2461-2610, 2461-2611, 2461-2612, 2461-2613, 2461-2614, 2461-2615, 2461-2616, 2461-2617, 2461-2618, 2461-2619, 2461-2620, 2461-2621, 2461-2622, 2461-2623, 2461-2624, 2461-2625, 2461-2626, 2461-2627, 2461-2628, 2461-2629, 2461-2630, 2461-2631, 2551-2566, 2551-2570, 2551-2571, 2551-2572, 2551-2573, 2551-2574, 2551-2575, 2551-2576, 2551-2577, 2551-2578, 2551-2579, 2551-2580, 2551-2581, 2551-2582, 2551-2583, 2551-2584, 2551-2585, 2551-2586, 2551-2587, 2551-2588, 2551-2589, 2551-2590, 2551-2591, 2551-2592, 2551-2593, 2551-2594, 2551-2595, 2551-2596, 2551-2597, 2551-2598, 2551-2599, 2551-2600, 2551-2601, 2551-2602, 2551-2603, 2551-2604, 2551-2605, 2551-2606, 2551-2607, 2551-2608, 2551-2609, 2551-2610, 2551-2611, 2551-2612, 2551-2613, 2551-2614, 2551-2615, 2551-2616, 2551-2617, 2551-2618, 2551-2619, 2551-2620, 2551-2621, 2551-2622, 2551-2623, 2551-2624, 2551-2625, 2551-2626, 2551-2627, 2551-2628, 2551-2629, 2551-2630, 2551-2631, 2553-2570, 2553-2571, 2553-2572, 2553-2573, 2553-2574, 2553-2575, 2553-2576, 2553-2577, 2553-2578, 2553-2579, 2553-2580, 2553-2581, 2553-2582, 2553-2583, 2553-2584, 2553-2585, 2553-2586, 2553-2587, 2553-2588, 2553-2589, 2553-2590, 2553-2591, 2553-2592, 2553-2593, 2553-2594, 2553-2595, 2553-2596, 2553-2597, 2553-2598, 2553-2599, 2553-2600, 2553-2601, 2553-2602, 2553-2603, 2553-2604, 2553-2605, 2553-2606, 2553-2607, 2553-2608, 2553-2609, 2553-2610, 2553-2611, 2553-2612, 2553-2613, 2553-2614, 2553-2615, 2553-2616, 2553-2617, 2553-2618, 2553-2619, 2553-2620, 2553-2621, 2553-2622, 2553-2623, 2553-2624, 2553-2625, 2553-2626, 2553-2627, 2553-2628, 2553-2629, 2553-2630, 2553-2631, 2554-2573, 2554-2574, 2554-2575, 2554-2576, 2554-2577, 2554-2578, 2554-2579, 2554-2580, 2554-2581, 2554-2582, 2554-2583, 2554-2584, 2554-2585, 2554-2586, 2554-2587, 2554-2588, 2554-2589, 2554-2590, 2554-2591, 2554-2592, 2554-2593, 2554-2594, 2554-2595, 2554-2596, 2554-2597, 2554-2598, 2554-2599, 2554-2600, 2554-2601, 2554-2602, 2554-2603, 2554-2604, 2554-2605, 2554-2606, 2554-2607, 2554-2608, 2554-2609, 2554-2610, 2554-2611, 2554-2612, 2554-2613, 2554-2614, 2554-2615, 2554-2616, 2554-2617, 2554-2618, 2554-2619, 2554-2620, 2554-2621, 2554-2622, 2554-2623, 2554-2624, 2554-2625, 2554-2626, 2554-2627, 2554-2628, 2554-2629, 2554-2630, 2554-2631, 2555-2572, 2555-2573, 2555-2574, 2555-2575, 2555-2576, 2555-2577, 2555-2578, 2555-2579, 2555-2580, 2555-2581, 2555-2582, 2555-2583, 2555-2584, 2555-2585, 2555-2586, 2555-2587, 2555-2588, 2555-2589, 2555-2590, 2555-2591, 2555-2592, 2555-2593, 2555-2594, 2555-2595, 2555-2596, 2555-2597, 2555-2598, 2555-2599, 2555-2600, 2555-2601, 2555-2602, 2555-2603, 2555-2604, 2555-2605, 2555-2606, 2555-2607, 2555-2608, 2555-2609, 2555-2610, 2555-2611, 2555-2612, 2555-2613, 2555-2614, 2555-2615, 2555-2616, 2555-2617, 2555-2618, 2555-2619, 2555-2620, 2555-2621, 2555-2622, 2555-2623, 2555-2624, 2555-2625, 2555-2626, 2555-2627, 2555-2628, 2555-2629, 2555-2630, 2555-2631, 2556-2573, 2556-2574, 2556-2575, 2556-2576, 2556-2577, 2556-2578, 2556-2579, 2556-2580, 2556-2581, 2556-2582, 2556-2583, 2556-2584, 2556-2585, 2556-2586, 2556-2587, 2556-2588, 2556-2589, 2556-2590, 2556-2591, 2556-2592, 2556-2593, 2556-2594, 2556-2595, 2556-2596, 2556-2597, 2556-2598, 2556-2599, 2556-2600, 2556-2601, 2556-2602, 2556-2603, 2556-2604, 2556-2605, 2556-2606, 2556-2607, 2556-2608, 2556-2609, 2556-2610, 2556-2611, 2556-2612, 2556-2613, 2556-2614, 2556-2615, 2556-2616, 2556-2617, 2556-2618, 2556-2619, 2556-2620, 2556-2621, 2556-2622, 2556-2623, 2556-2624, 2556-2625, 2556-2626, 2556-2627, 2556-2628, 2556-2629, 2556-2630, 2556-2631, 2557-2574, 2557-2575, 2557-2576, 2557-2577, 2557-2578, 2557-2579, 2557-2580, 2557-2581, 2557-2582, 2557-2583, 2557-2584, 2557-2585, 2557-2586, 2557-2587, 2557-2588, 2557-2589, 2557-2590, 2557-2591, 2557-2592, 2557-2593, 2557-2594, 2557-2595, 2557-2596, 2557-2597, 2557-2598, 2557-2599, 2557-2600, 2557-2601, 2557-2602, 2557-2603, 2557-2604, 2557-2605, 2557-2606, 2557-2607, 2557-2608, 2557-2609, 2557-2610, 2557-2611, 2557-2612, 2557-2613, 2557-2614, 2557-2615, 2557-2616, 2557-2617, 2557-2618, 2557-2619, 2557-2620, 2557-2621, 2557-2622, 2557-2623, 2557-2624, 2557-2625, 2557-2626, 2557-2627, 2557-2628, 2557-2629, 2557-2630, 2557-2631, 2558-2575, 2558-2576, 2558-2577, 2558-2578, 2558-2579, 2558-2580, 2558-2581, 2558-2582, 2558-2583, 2558-2584, 2558-2585, 2558-2586, 2558-2587, 2558-2588, 2558-2589, 2558-2590, 2558-2591, 2558-2592, 2558-2593, 2558-2594, 2558-2595, 2558-2596, 2558-2597, 2558-2598, 2558-2599, 2558-2600, 2558-2601, 2558-2602, 2558-2603, 2558-2604, 2558-2605, 2558-2606, 2558-2607, 2558-2608, 2558-2609, 2558-2610, 2558-2611, 2558-2612, 2558-2613, 2558-2614, 2558-2615, 2558-2616, 2558-2617, 2558-2618, 2558-2619, 2558-2620, 2558-2621, 2558-2622, 2558-2623, 2558-2624, 2558-2625, 2558-2626, 2558-2627, 2558-2628, 2558-2629, 2558-2630, 2558-2631, 2559-2576, 2559-2577, 2559-2578, 2559-2579, 2559-2580, 2559-2581, 2559-2582, 2559-2583, 2559-2584, 2559-2585, 2559-2586, 2559-2587, 2559-2588, 2559-2589, 2559-2590, 2559-2591, 2559-2592, 2559-2593, 2559-2594, 2559-2595, 2559-2596, 2559-2597, 2559-2598, 2559-2599, 2559-2600, 2559-2601, 2559-2602, 2559-2603, 2559-2604, 2559-2605, 2559-2606, 2559-2607, 2559-2608, 2559-2609, 2559-2610, 2559-2611, 2559-2612, 2559-2613, 2559-2614, 2559-2615, 2559-2616, 2559-2617, 2559-2618, 2559-2619, 2559-2620, 2559-2621, 2559-2622, 2559-2623, 2559-2624, 2559-2625, 2559-2626, 2559-2627, 2559-2628, 2559-2629, 2559-2630, 2559-2631, 2560-2577, 2560-2578, 2560-2579, 2560-2580, 2560-2581, 2560-2582, 2560-2583, 2560-2584, 2560-2585, 2560-2586, 2560-2587, 2560-2588, 2560-2589, 2560-2590, 2560-2591, 2560-2592, 2560-2593, 2560-2594, 2560-2595, 2560-2596, 2560-2597, 2560-2598, 2560-2599, 2560-2600, 2560-2601, 2560-2602, 2560-2603, 2560-2604, 2560-2605, 2560-2606, 2560-2607, 2560-2608, 2560-2609, 2560-2610, 2560-2611, 2560-2612, 2560-2613, 2560-2614, 2560-2615, 2560-2616, 2560-2617, 2560-2618, 2560-2619, 2560-2620, 2560-2621, 2560-2622, 2560-2623, 2560-2624, 2560-2625, 2560-2626, 2560-2627, 2560-2628, 2560-2629, 2560-2630, 2560-2631, 2561-2578, 2561-2579, 2561-2580, 2561-2581, 2561-2582, 2561-2583, 2561-2584, 2561-2585, 2561-2586, 2561-2587, 2561-2588, 2561-2589, 2561-2590, 2561-2591, 2561-2592, 2561-2593, 2561-2594, 2561-2595, 2561-2596, 2561-2597, 2561-2598, 2561-2599, 2561-2600, 2561-2601, 2561-2602, 2561-2603, 2561-2604, 2561-2605, 2561-2606, 2561-2607, 2561-2608, 2561-2609, 2561-2610, 2561-2611, 2561-2612, 2561-2613, 2561-2614, 2561-2615, 2561-2616, 2561-2617, 2561-2618, 2561-2619, 2561-2620, 2561-2621, 2561-2622, 2561-2623, 2561-2624, 2561-2625, 2561-2626, 2561-2627, 2561-2628, 2561-2629, 2561-2630, 2561-2631, 2562-2577, 2562-2578, 2562-2579, 2562-2580, 2562-2581, 2562-2582, 2562-2583, 2562-2584, 2562-2585, 2562-2586, 2562-2587, 2562-2588, 2562-2589, 2562-2590, 2562-2591, 2562-2592, 2562-2593, 2562-2594, 2562-2595, 2562-2596, 2562-2597, 2562-2598, 2562-2599, 2562-2600, 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2592-2614, 2592-2615, 2592-2616, 2592-2617, 2592-2618, 2592-2619, 2592-2620, 2592-2621, 2592-2622, 2592-2623, 2592-2624, 2592-2625, 2592-2626, 2592-2627, 2592-2628, 2592-2629, 2592-2630, 2592-2631, 2593-2608, 2593-2612, 2593-2613, 2593-2614, 2593-2615, 2593-2616, 2593-2617, 2593-2618, 2593-2619, 2593-2620, 2593-2621, 2593-2622, 2593-2623, 2593-2624, 2593-2625, 2593-2626, 2593-2627, 2593-2628, 2593-2629, 2593-2630, 2593-2631, 2594-2612, 2594-2613, 2594-2614, 2594-2615, 2594-2616, 2594-2617, 2594-2618, 2594-2619, 2594-2620, 2594-2621, 2594-2622, 2594-2623, 2594-2624, 2594-2625, 2594-2626, 2594-2627, 2594-2628, 2594-2629, 2594-2630, 2594-2631, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2595-2615, 2595-2616, 2595-2617, 2595-2618, 2595-2619, 2595-2620, 2595-2621, 2595-2622, 2595-2623, 2595-2624, 2595-2625, 2595-2626, 2595-2627, 2595-2628, 2595-2629, 2595-2630, 2595-2631, 2596-2614, 2596-2615, 2596-2616, 2596-2617, 2596-2618, 2596-2619, 2596-2620, 2596-2621, 2596-2622, 2596-2623, 2596-2624, 2596-2625, 2596-2626, 2596-2627, 2596-2628, 2596-2629, 2596-2630, 2596-2631, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2597-2617, 2597-2618, 2597-2619, 2597-2620, 2597-2621, 2597-2622, 2597-2623, 2597-2624, 2597-2625, 2597-2626, 2597-2627, 2597-2628, 2597-2629, 2597-2630, 2597-2631, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2598-2618, 2598-2619, 2598-2620, 2598-2621, 2598-2622, 2598-2623, 2598-2624, 2598-2625, 2598-2626, 2598-2627, 2598-2628, 2598-2629, 2598-2630, 2598-2631, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2599-2619, 2599-2620, 2599-2621, 2599-2622, 2599-2623, 2599-2624, 2599-2625, 2599-2626, 2599-2627, 2599-2628, 2599-2629, 2599-2630, 2599-2631, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2600-2620, 2600-2621, 2600-2622, 2600-2623, 2600-2624, 2600-2625, 2600-2626, 2600-2627, 2600-2628, 2600-2629, 2600-2630, 2600-2631, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2601-2621, 2601-2622, 2601-2623, 2601-2624, 2601-2625, 2601-2626, 2601-2627, 2601-2628, 2601-2629, 2601-2630, 2601-2631, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2602-2622, 2602-2623, 2602-2624, 2602-2625, 2602-2626, 2602-2627, 2602-2628, 2602-2629, 2602-2630, 2602-2631, 2603-2620, 2603-2621, 2603-2622, 2603-2623, 2603-2624, 2603-2625, 2603-2626, 2603-2627, 2603-2628, 2603-2629, 2603-2630, 2603-2631, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2604-2624, 2604-2625, 2604-2626, 2604-2627, 2604-2628, 2604-2629, 2604-2630, 2604-2631, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2605-2625, 2605-2626, 2605-2627, 2605-2628, 2605-2629, 2605-2630, 2605-2631, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2606-2626, 2606-2627, 2606-2628, 2606-2629, 2606-2630, 2606-2631, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2607-2627, 2607-2628, 2607-2629, 2607-2630, 2607-2631, 2608-2623, 2608-2624, 2608-2625, 2608-2626, 2608-2627, 2608-2628, 2608-2629, 2608-2630, 2608-2631, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2609-2629, 2609-2630, 2609-2631, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2610-2630, 2610-2631, 2611-2626, 2611-2627, 2611-2628, 2611-2629, 2611-2630, 2611-2631, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2631, or 2616-2631. In certain embodiments, antisense compounds or oligonucleotides target at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobases within the aforementioned nucleobase regions.

[0122] In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or oligonucleotides, display at least 50% inhibition: 30-49, 48-63, 150-169, 151-170, 152-171, 154-169, 154-173, 156-171, 156-175, 157-176, 158-173, 158-177, 480-499, 600-619, 638-657, 644-663, 738-757, 1089-1108, 1135-1154, 1141-1160, 1147-1166, 1150-1169, 1153-1172, 1159-1178, 1162-1181, 1165-1184, 1171-1186, 1171-1190, 1173-1188, 1173-1192, 1175-1190, 1175-1194, 1177-1196, 1183-1202, 1208-1227, 1235-1254, 1298-1317, 1304-1323, 1310-1329, 1316-1335, 1319-1338, 1322-1341, 1328-1347, 1349-1368, 1355-1374, 1393-1412, 1396-1415, 1399-1418, 1405-1424, 1421-1440, 1621-1640, 1646-1665, 1646-1665, 1647-1666, 1689-1708, 1749-1768, 1763-1782, 1912-1931, 2073-2092, 2085-2104, 2166-2185, 2172-2191, 2189-2208, 2191-2210, 2193-2212, 2195-2210, 2195-2214, 2196-2215, 2197-2212, 2197-2216, 2202-2221, 2223-2238, 2223-2242, 2225-2240, 2226-2245, 2227-2242, 2227-2246, 2238-2257, 2241-2260, 2267-2286, 2361-2380, 2388-2407, 2397-2416, 2448-2467, 2453-2472, 2455-2474, 2457-2472, 2457-2476, 2459-2474, 2459-2478, 2461-2476, 2461-2480, 2532-2551, 2550-2569, 2551-2566, 2551-2570, 2552-2568, 2552-2570, 2552-2571, 2553-2568, 2553-2570, 2553-2571, 2553-2572, 2554-2571, 2554-2572, 2554-2573, 2555-2570, 2555-2572, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2573, 2557-2574, 2557-2575, 2557-2576, 2558-2575, 2558-2576, 2558-2577, 2559-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2576, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2578, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2566-2585, 2567-2582, 2567-2584, 2567-2586, 2568-2583, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2585, 2570-2587, 2570-2589, 2571-2586, 2571-2588, 2571-2590, 2572-2589, 2572-2590, 2572-2591, 2573-2590, 2573-2592, 2574-2590, 2574-2591, 2574-2593, 2575-2590, 2575-2591, 2575-2592, 2575-2594, 2576-2593, 2576-2595, 2577-2594, 2577-2595, 2577-2596, 2578-2594, 2578-2596, 2578-2597, 2579-2598, 2580-2596, 2580-2597, 2580-2598, 2580-2599, 2581-2597, 2581-2598, 2581-2599, 2581-2600, 2582-2598, 2582-2599, 2582-2600, 2582-2601, 2583-2599, 2583-2600, 2583-2601, 2583-2602, 2584-2600, 2584-2601, 2584-2602, 2584-2603, 2585-2601, 2585-2603, 2585-2604, 2586-2601, 2586-2602, 2586-2604, 2586-2605, 2587-2602, 2587-2603, 2587-2605, 2587-2606, 2588-2603, 2588-2604, 2588-2605, 2588-2606, 2588-2607, 2589-2604, 2589-2605, 2589-2606, 2589-2607, 2589-2608, 2590-2605, 2590-2606, 2590-2607, 2590-2608, 2590-2609, 2590-2609, 2591-2607, 2591-2608, 2591-2609, 2591-2610, 2592-2607, 2592-2608, 2592-2609, 2592-2610, 2592-2611, 2593-2608, 2593-2609, 2593-2610, 2593-2612, 2594-2609, 2594-2610, 2594-2611, 2594-2612, 2594-2613, 2595-2610, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2596-2611, 2596-2612, 2596-2613, 2596-2614, 2596-2615, 2597-2612, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2602-2617, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2603-2618, 2603-2619, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2626, 2608-2627, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2611-2626, 2611-2627, 2611-2628, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2631, and 2616-2631.

[0123] In certain embodiments, the following nucleotide regions of SEQ ID NO: 2, when targeted by antisense compounds or oligonucleotides, display at least 50% inhibition: 1608-1627, 1685-1704, 1686-1705, 1751-1770, 1769-1784, 1871-1890, 1872-1891, 1873-1892, 1875-1890, 1875-1894, 1877-1892, 1877-1896, 1878-1897, 1879-1894, 1879-1898, 2288-2307, 2808-2827, 2846-2865, 2852-2871, 2946-2965, 3773-3792, 3819-3838, 3825-3844, 3831-3850, 3834-3853, 3837-3856, 3843-3862, 4151-4166, 4151-4170, 4153-4172, 4159-4178, 4184-4203, 4211-4230, 4609-4628, 4612-4631, 4615-4634, 4621-4640, 4642-4661, 4648-4667, 4686-4705, 4689-4708, 4692-4711, 4698-4717, 4714-4733, 5270-5289, 5295-5314, 5296-5315, 5830-5849, 5890-5909, 5904-5923, 6406-6425, 6662-6681, 6674-6693, 6954-6973, 6960-6979, 6977-6996, 6979-6998, 6981-7000, 6983-6998, 6983-7002, 6984-7003, 6985-7000, 6985-7004, 6990-7009, 7122-7141, 7125-7144, 7151-7170, 7353-7372, 7362-7381, 7683-7702, 7688-7707, 7690-7709, 7692-7707, 7692-7711, 7694-7709, 7694-7713, 7696-7711, 7696-7715, 7767-7786, 7785-7804, 7786-7801, 7787-7803, 7787-7805, 7787-7806, 7788-7803, 7788-7805, 7788-7806, 7788-7807, 7789-7806, 7789-7807, 7789-7808, 7790-7805, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7808, 7792-7809, 7792-7810, 7792-7811, 7793-7810, 7793-7811, 7793-7812, 7794-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7811, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7813, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7801-7820, 7802-7817, 7802-7819, 7802-7821, 7803-7818, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7820, 7805-7822, 7805-7824, 7806-7821, 7806-7823, 7806-7825, 7807-7824, 7807-7825, 7807-7826, 7808-7825, 7808-7827, 7809-7825, 7809-7826, 7809-7828, 7810-7825, 7810-7826, 7810-7827, 7810-7829, 7811-7828, 7811-7830, 7812-7829, 7812-7830, 7812-7831, 7813-7829, 7813-7831, 7813-7832, 7814-7833, 7815-7831, 7815-7832, 7815-7833, 7815-7834, 7816-7832, 7816-7833, 7816-7834, 7816-7835, 7817-7833, 7817-7834, 7817-7835, 7817-7836, 7818-7834, 7818-7835, 7818-7836, 7818-7837, 7819-7835, 7819-7836, 7819-7837, 7819-7838, 7820-7836, 7820-7838, 7820-7839, 7821-7836, 7821-7837, 7821-7839, 7821-7840, 7822-7837, 7822-7838, 7822-7840, 7822-7841, 7823-7838, 7823-7839, 7823-7839, 7823-7840, 7823-7841, 7823-7842, 7824-7839, 7824-7840, 7824-7840, 7824-7841, 7824-7842, 7824-7843, 7825-7840, 7825-7841, 7825-7842, 7825-7843, 7825-7844, 7826-7842, 7826-7843, 7826-7844, 7826-7845, 7827-7842, 7827-7843, 7827-7844, 7827-7845, 7827-7846, 7828-7843, 7828-7844, 7828-7845, 7828-7847, 7829-7844, 7829-7845, 7829-7846, 7829-7847, 7829-7848, 7830-7845, 7830-7846, 7830-7847, 7830-7848, 7830-7849, 7831-7846, 7831-7847, 7831-7848, 7831-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7850, 7834-7851, 7834-7852, 7834-7853, 7835-7850, 7835-7851, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7853, 7836-7854, 7836-7855, 7837-7852, 7837-7853, 7837-7854, 7837-7855, 7837-7856, 7838-7853, 7838-7854, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7861, 7843-7862, 7844-7859, 7844-7860, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7845-7862, 7846-7861, and 7846-7862.

[0124] In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or oligonucleotides, display at least 60% inhibition: 48-63, 150-169, 152-171, 154-169, 154-173, 156-171, 156-175, 158-173, 158-177, 600-619, 1135-1154, 1141-1160, 1147-1166, 1153-1172, 1171-1186, 1173-1188, 1175-1190, 1749-1768, 1763-1782, 1763-1782, 1912-1931, 2189-2208, 2191-2210, 2193-2212, 2195-2210, 2195-2214, 2197-2212, 2197-2216, 2223-2238, 2225-2240, 2227-2242, 2238-2257, 2448-2467, 2453-2472, 2455-2474, 2457-2472, 2457-2476, 2459-2474, 2459-2478, 2461-2476, 2461-2480, 2550-2569. 2551-2566, 2552-2571, 2553-2568, 2553-2570, 2553-2571, 2553-2572, 2554-2571, 2554-2572, 2554-2573, 2555-2572, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2574, 2557-2575, 2557-2576, 2558-2575, 2558-2576, 2558-2577, 2559-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2578, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2566-2585, 2567-2582, 2567-2584, 2567-2586, 2568-2583, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2587, 2570-2589, 2571-2588, 2572-2590, 2572-2591, 2573-2590, 2573-2592, 2574-2591, 2574-2593, 2575-2590, 2575-2592, 2575-2594, 2576-2593, 2576-2595, 2577-2594, 2577-2595, 2577-2596, 2578-2594, 2578-2597, 2579-2598, 2580-2596, 2580-2597, 2580-2598, 2580-2599, 2581-2597, 2581-2598, 2581-2599, 2581-2600, 2582-2598, 2582-2599, 2582-2600, 2582-2601, 2583-2599, 2583-2600, 2583-2601, 2583-2602, 2584-2600, 2584-2602, 2584-2603, 2585-2601, 2585-2603, 2585-2604, 2586-2602, 2586-2604, 2586-2605, 2587-2603, 2587-2605, 2587-2606, 2588-2603, 2588-2604, 2588-2606, 2588-2607, 2589-2605, 2589-2606, 2589-2607, 2589-2608, 2590-2605, 2590-2606, 2590-2607, 2590-2608, 2590-2609, 2591-2607, 2591-2609, 2591-2610, 2592-2608, 2592-2609, 2592-2611, 2593-2608, 2593-2609, 2593-2612, 2594-2609, 2594-2610, 2594-2611, 2594-2612, 2594-2613, 2595-2610, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2596-2611, 2596-2612, 2596-2613, 2596-2614, 2596-2615, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2602-2617, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2603-2618, 2603-2619, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2625, 2608-2626, 2608-2627, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2611-2626, 2611-2626, 2611-2627, 2611-2628, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2630, 2615-2631, 2615-2631, and 2616-2631.

[0125] In certain embodiments, the following nucleotide regions of SEQ ID NO: 2, when targeted by antisense compounds or oligonucleotides, display at least 60% inhibition: 1685-1704, 1686-1705, 1769-1784, 1871-1890, 1873-1892, 1875-1890, 1875-1894, 1877-1892, 1877-1896, 1879-1894, 1879-1898, 2808-2827, 3819-3838, 3825-3844, 3831-3850, 3837-3856, 4151-4166, 5890-5909, 5904-5923, 5904-5923, 6406-6425, 6977-6996, 6979-6998, 6981-7000, 6983-6998, 6983-7002, 6985-7000, 6985-7004, 7122-7141, 7683-7702, 7688-7707, 7690-7709, 7692-7707, 7692-7711, 7694-7709, 7696-7711, 7696-7715, 7786-7801, 7787-7806, 7788-7803, 7788-7805, 7788-7806, 7788-7807, 7789-7806, 7789-7807, 7789-7808, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7809, 7792-7810, 7792-7811, 7793-7810, 7793-7811, 7793-7812, 7794-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7813, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7801-7820, 7802-7817, 7802-7819, 7802-7821, 7803-7818, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7822, 7805-7824, 7806-7823, 7806-7825, 7807-7824, 7807-7825, 7807-7826, 7808-7825, 7808-7827, 7809-7826, 7809-7828, 7810-7825, 7810-7827, 7810-7829, 7811-7828, 7811-7830, 7812-7829, 7812-7830, 7812-7831, 7813-7829, 7813-7832, 7814-7833, 7815-7831, 7815-7832, 7815-7833, 7815-7834, 7816-7832, 7816-7833, 7816-7834, 7816-7835, 7817-7833, 7817-7834, 7817-7835, 7817-7836, 7818-7834, 7818-7835, 7818-7836, 7818-7837, 7819-7835, 7819-7837, 7819-7838, 7820-7836, 7820-7838, 7820-7839, 7821-7837, 7821-7839, 7821-7840, 7822-7838, 7822-7840, 7822-7841, 7823-7838, 7823-7839, 7823-7841, 7823-7842, 7824-7840, 7824-7841, 7824-7842, 7824-7843, 7825-7840, 7825-7841, 7825-7842, 7825-7843, 7825-7844, 7826-7842, 7826-7844, 7826-7845, 7827-7843, 7827-7844, 7827-7846, 7828-7843, 7828-7844, 7828-7847, 7829-7844, 7829-7845, 7829-7846, 7829-7847, 7829-7848, 7830-7845, 7830-7846, 7830-7847, 7830-7848, 7830-7849, 7831-7846, 7831-7847, 7831-7848, 7831-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7850, 7834-7851, 7834-7852, 7834-7853, 7835-7850, 7835-7851, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7853, 7836-7854, 7836-7855, 7837-7852, 7837-7853, 7837-7854, 7837-7855, 7837-7856, 7838-7853, 7838-7854, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7861, 7843-7862, 7844-7859, 7844-7860, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7845-7862, 7846-7861, 7846-7862, and 7847-7862.

[0126] In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or oligonucleotides, display at least 70% inhibition: 48-63, 150-169, 152-171, 154-169, 154-173, 156-171, 156-175, 158-173, 158-177, 1135-1154, 1141-1160, 1147-1166, 1171-1186, 1173-1188, 1175-1190, 1749-1768, 1763-1782, 1912-1931, 2193-2212, 2195-2210, 2195-2214, 2197-2212, 2197-2216, 2223-2238, 2225-2240, 2227-2242, 2453-2472, 2455-2474, 2457-2472, 2457-2476, 2459-2474, 2461-2476, 2461-2480, 2550-2569, 2551-2566, 2552-2571, 2553-2570, 2553-2571, 2553-2572, 2554-2571, 2554-2572, 2554-2573, 2554-2573, 2555-2572, 2555-2574, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2574, 2557-2576, 2558-2575, 2558-2576, 2558-2577, 2559-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2578, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2566-2585, 2567-2582, 2567-2584, 2567-2586, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2587, 2570-2589, 2571-2588, 2571-2590, 2572-2589, 2572-2591, 2573-2590, 2573-2592, 2574-2591, 2574-2593, 2575-2592, 2575-2594, 2576-2593, 2576-2595, 2577-2594, 2577-2596, 2578-2597, 2579-2598, 2580-2596, 2580-2598, 2580-2599, 2581-2597, 2581-2600, 2582-2598, 2582-2600, 2582-2601, 2583-2599, 2583-2601, 2583-2602, 2584-2600, 2584-2602, 2584-2603, 2585-2601, 2585-2603, 2585-2604, 2586-2605, 2587-2606, 2588-2604, 2588-2606, 2588-2607, 2589-2605, 2589-2606. 2589-2607, 2589-2608, 2590-2605, 2590-2606, 2590-2607, 2590-2609, 2591-2607, 2591-2610, 2592-2611, 2593-2608, 2593-2612, 2594-2609, 2594-2610, 2594-2612, 2594-2613, 2595-2610, 2595-2611, 2595-2612, 2595-2613, 2595-2614, 2596-2611, 2596-2614, 2596-2615, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2615, 2599-2616, 2599-2617, 2599-2618, 2600-2615, 2600-2616, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2618, 2601-2619, 2601-2620, 2602-2617, 2602-2618, 2602-2619, 2602-2620, 2602-2621, 2603-2619, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2626, 2608-2627, 2609-2624, 2609-2625, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2627, 2610-2628, 2610-2629, 2611-2626, 2611-2627, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2629, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2630, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, 2615-2630, 2615-2631, and 2616-2631.

[0127] In certain embodiments, the following nucleotide regions of SEQ ID NO: 2, when targeted by antisense compounds or oligonucleotides, display at least 70% inhibition: 1685-1704, 1686-1705, 1769-1784, 1871-1890, 1873-1892, 1875-1890, 1875-1894, 1877-1892, 1877-1896, 1879-1894, 1879-1898, 3819-3838, 3825-3844, 3831-3850, 4151-4166, 5890-5909, 5904-5923, 5904-5923, 6406-6425, 6983-6998, 6983-7002, 6985-7000, 6985-7004, 7688-7707, 7690-7709, 7692-7707, 7692-7711, 7694-7709, 7696-7711, 7696-7715, 7786-7801, 7787-7806, 7788-7805, 7788-7806, 7788-7807, 7789-7806, 7789-7807, 7789-7808, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7809, 7792-7811, 7793-7810, 7793-7811, 7793-7812, 7794-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7813, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7801-7820, 7802-7817, 7802-7819, 7802-7821, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7822, 7805-7824, 7806-7823, 7806-7825, 7807-7824, 7807-7826, 7808-7825, 7808-7827, 7809-7826, 7809-7828, 7810-7827, 7811-7828, 7811-7830, 7812-7829, 7812-7831, 7813-7832, 7814-7833, 7815-7831, 7815-7833, 7815-7834, 7816-7832, 7816-7835, 7817-7833, 7817-7835, 7817-7836, 7818-7834, 7818-7836, 7818-7837, 7819-7835, 7819-7837, 7819-7838, 7820-7836, 7820-7838, 7820-7839, 7821-7840, 7822-7841, 7823-7839, 7823-7841, 7823-7842, 7824-7840, 7824-7841, 7824-7842, 7824-7843, 7825-7840, 7825-7841, 7825-7842, 7825-7844, 7826-7842, 7826-7845, 7827-7846, 7828-7843, 7828-7847, 7829-7844, 7829-7845, 7829-7847, 7829-7848, 7830-7845, 7830-7846, 7830-7847, 7830-7848, 7830-7849, 7831-7846, 7831-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7850, 7834-7851, 7834-7852, 7834-7853, 7835-7850, 7835-7851, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7853, 7836-7854, 7836-7855, 7837-7852, 7837-7853, 7837-7854, 7837-7855, 7837-7856, 7838-7854, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7861, 7843-7862, 7844-7859, 7844-7860, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7845-7862, 7846-7861, 7846-7862, and 7847-7862.

[0128] In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or oligonucleotides, display at least 80% inhibition: 152-171, 154-169, 156-171, 158-173, 1135-1154, 1171-1186, 1173-1188, 1175-1190, 1763-1782, 1912-1931, 2197-2212, 2223-2238, 2225-2240, 2227-2242, 2457-2472, 2459-2474, 2461-2476, 2551-2566, 2553-2570, 2553-2571, 2553-2572, 2554-2573, 2555-2572, 2555-2574, 2556-2573, 2556-2574, 2556-2575, 2557-2574, 2557-2576, 2558-2575, 2558-2576, 2559-2577, 2559-2578, 2560-2577, 2560-2578, 2560-2579, 2561-2578, 2561-2579, 2561-2580, 2562-2577, 2562-2579, 2562-2581, 2563-2580, 2563-2582, 2564-2581, 2564-2583, 2565-2584, 2566-2583, 2567-2584, 2567-2586, 2568-2585, 2568-2587, 2569-2586, 2569-2588, 2570-2587, 2571-2588, 2571-2590, 2572-2589, 2572-2591, 2573-2590, 2573-2592, 2574-2591, 2574-2593, 2575-2592, 2576-2593, 2576-2595, 2577-2594, 2577-2596, 2578-2597, 2580-2598, 2580-2599, 2581-2597, 2581-2600, 2582-2601, 2583-2602, 2584-2603, 2585-2604, 2586-2605, 2587-2606, 2588-2607, 2589-2608, 2590-2606, 2590-2607, 2590-2609, 2591-2610, 2592-2611, 2593-2608, 2593-2612, 2594-2613, 2595-2611, 2595-2614, 2596-2615, 2597-2612, 2597-2613, 2597-2614, 2597-2615, 2597-2616, 2598-2613, 2598-2613, 2598-2614, 2598-2615, 2598-2616, 2598-2617, 2599-2614, 2599-2617, 2599-2618, 2600-2615, 2600-2617, 2600-2618, 2600-2619, 2601-2616, 2601-2617, 2601-2619, 2601-2620, 2602-2618, 2602-2621, 2603-2620, 2603-2621, 2603-2622, 2604-2619, 2604-2620, 2604-2621, 2604-2622, 2604-2623, 2605-2620, 2605-2621, 2605-2622, 2605-2623, 2605-2624, 2606-2621, 2606-2622, 2606-2623, 2606-2624, 2606-2625, 2607-2622, 2607-2623, 2607-2624, 2607-2625, 2607-2626, 2608-2623, 2608-2624, 2608-2625, 2608-2627, 2609-2624, 2609-2626, 2609-2627, 2609-2628, 2610-2625, 2610-2626, 2610-2628, 2610-2629, 2611-2626, 2611-2627, 2611-2629, 2611-2630, 2612-2627, 2612-2628, 2612-2630, 2612-2631, 2613-2628, 2613-2629, 2613-2631, 2614-2629, 2614-2630, 2614-2631, 2615-2630, and 2616-2631.

[0129] In certain embodiments, the following nucleotide regions of SEQ ID NO: 2, when targeted by antisense compounds or oligonucleotides, display at least 80% inhibition: 1685-1704, 1686-1705, 1873-1892, 1875-1890, 1877-1892, 1879-1894, 3819-3838, 4151-4166, 5904-5923, 6406-6425, 6985-7000, 7692-7707, 7694-7709, 7696-7711, 7786-7801, 7788-7805, 7788-7806, 7788-7807, 7789-7808, 7790-7807, 7790-7809, 7791-7808, 7791-7809, 7791-7810, 7792-7809, 7792-7811, 7793-7810, 7793-7811, 7794-7812, 7794-7813, 7795-7812, 7795-7813, 7795-7814, 7796-7813, 7796-7814, 7796-7815, 7797-7812, 7797-7814, 7797-7816, 7798-7815, 7798-7817, 7799-7816, 7799-7818, 7800-7819, 7801-7818, 7802-7819, 7802-7821, 7803-7820, 7803-7822, 7804-7821, 7804-7823, 7805-7822, 7806-7823, 7806-7825, 7807-7824, 7807-7826, 7808-7825, 7808-7827, 7809-7826, 7809-7828, 7810-7827, 7811-7828, 7812-7829, 7812-7831, 7813-7832, 7814-7833, 7815-7834, 7816-7832, 7816-7835, 7817-7836, 7818-7837, 7819-7838, 7820-7839, 7821-7840, 7822-7841, 7823-7842, 7824-7843, 7825-7841, 7825-7842, 7825-7844, 7826-7845, 7827-7846, 7828-7843, 7828-7847, 7829-7848, 7830-7846, 7830-7849, 7831-7850, 7832-7847, 7832-7848, 7832-7849, 7832-7850, 7832-7851, 7833-7848, 7833-7849, 7833-7850, 7833-7851, 7833-7852, 7834-7849, 7834-7852, 7834-7853, 7835-7850, 7835-7852, 7835-7853, 7835-7854, 7836-7851, 7836-7852, 7836-7854, 7836-7855, 7837-7853, 7837-7856, 7838-7855, 7838-7856, 7838-7857, 7839-7854, 7839-7855, 7839-7856, 7839-7857, 7839-7858, 7840-7855, 7840-7856, 7840-7857, 7840-7858, 7840-7859, 7841-7856, 7841-7857, 7841-7858, 7841-7859, 7841-7860, 7842-7857, 7842-7858, 7842-7859, 7842-7860, 7842-7861, 7843-7858, 7843-7859, 7843-7860, 7843-7862, 7844-7859, 7844-7861, 7844-7862, 7845-7860, 7845-7861, 7846-7862, and 7847-7862.

[0130] In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or oligonucleotides, display at least 90% inhibition: 154-169, 156-171, 158-173, 1135-1154, 1171-1186, 1173-1188, 1763-1782, 1912-1931, 2223-2238, 2227-2242, 2459-2474, 2461-2476, 2554-2573, 2555-2574, 2560-2577, 2561-2578, 2561-2579, 2562-2581, 2563-2580, 2563-2582, 2564-2581, 2566-2583, 2567-2584, 2568-2585, 2568-2587, 2569-2586, 2570-2587, 2576-2593, 2577-2594, 2577-2596, 2578-2597, 2580-2599, 2581-2600, 2582-2601, 2583-2602, 2584-2603, 2586-2605, 2587-2605, 2587-2606, 2588-2607, 2589-2608, 2590-2607, 2590-2609, 2592-2611, 2595-2614, 2596-2615, 2597-2612, 2597-2613, 2597-2615, 2597-2616, 2598-2613, 2598-2613, 2598-2617, 2599-2614, 2599-2618, 2600-2615, 2600-2619, 2601-2617, 2601-2620, 2602-2621, 2603-2622, 2604-2623, 2605-2621, 2605-2622, 2605-2624, 2606-2625, 2607-2626, 2608-2623, 2608-2625, 2609-2628, 2611-2627, 2611-2630, 2612-2628, 2612-2631, 2613-2629, 2614-2629, 2615-2630, and 2616-2631.

[0131] In certain embodiments, the following nucleotide regions of SEQ ID NO: 2, when targeted by antisense compounds or oligonucleotides, display at least 90% inhibition: 1685-1704, 1686-1705, 1875-1890, 1877-1892, 1879-1894, 3819-3838, 5904-5923, 6406-6425, 7694-7709, 7696-7711, 7789-7808, 7790-7809, 7795-7812, 7795-7813, 7796-7813, 7796-7814, 7797-7814, 7797-7816, 7798-7815, 7798-7817, 7799-7816, 7801-7818, 7802-7819, 7803-7820, 7803-7822, 7804-7821, 7805-7822, 7811-7828, 7812-7829, 7812-7831, 7813-7832, 7815-7834, 7818-7837, 7819-7838, 7821-7840, 7822-7840, 7822-7841, 7825-7842, 7832-7847, 7832-7848, 7832-7850, 7833-7848, 7833-7852, 7834-7849, 7834-7853, 7835-7850, 7836-7852, 7836-7855, 7837-7856, 7838-7856, 7839-7857, 7839-7858, 7840-7856, 7840-7857, 7840-7859, 7843-7858, 7843-7860, and 7846-7862.

[0132] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 50% inhibition of a CFB mRNA, ISIS NOs: 516350, 532614, 532632, 532635, 532638, 532639, 532686, 532687, 532688, 532689, 532690, 532691, 532692, 532692, 532693, 532694, 532695, 532696, 532697, 532698, 532699, 532700, 532701, 532702, 532703, 532704, 532705, 532706, 532707, 532770, 532775, 532778, 532780, 532791, 532800, 532809, 532810, 532811, 532917, 532952, 588509, 588510, 588511, 588512, 588513, 588514, 588515, 588516, 588517, 588518, 588519, 588520, 588522, 588523, 588524, 588525, 588527, 588528, 588529, 588530, 588531, 588532, 588533, 588534, 588535, 588536, 588537, 588538, 588539, 588540, 588541, 588542, 588543, 588544, 588545, 588546, 588547, 588548, 588549, 588550, 588551, 588552, 588553, 588554, 588555, 588556, 588557, 588558, 588559, 588560, 588561, 588562, 588563, 588564, 588565, 588566, 588567, 588568, 588569, 588570, 588571, 588572, 588573, 588574, 588575, 588576, 588577, 588580, 588581, 588585, 588586, 588589, 588590, 588599, 588603, 588606, 588608, 588610, 588614, 588616, 588628, 588631, 588632, 588634, 588636, 588638, 588640, 588645, 588646, 588654, 588656, 588658, 588660, 588662, 588664, 588670, 588672, 588676, 588682, 588688, 588696, 588698, 588807, 588808, 588809, 588813, 588814, 588815, 588819, 588820, 588822, 588823, 588838, 588839, 588840, 588841, 588842, 588846, 588847, 588848, 588849, 588850, 588851, 588852, 588853, 588854, 588855, 588856, 588857, 588858, 588859, 588860, 588861, 588862, 588863, 588864, 588865, 588866, 588867, 588868, 588870, 588871, 588872, 588873, 588874, 588875, 588876, 588877, 588878, 588879, 588880, 588881, 588882, 588883, 588884, 598999, 599000, 599001, 599002, 599003, 599004, 599005, 599006, 599007, 599008, 599009, 599010, 599011, 599012, 599013, 599014, 599015, 599018, 599019, 599023, 599024, 599025, 599026, 599027, 599028, 599029, 599030, 599031, 599032, 599033, 599034, 599035, 599058, 599062, 599063, 599064, 599065, 599070, 599071, 599072, 599073, 599074, 599076, 599077, 599078, 599079, 599080, 599081, 599082, 599083, 599084, 599085, 599086, 599087, 599088, 599089, 599090, 599091, 599092, 599093, 599094, 599095, 599096, 599097, 599098, 599102, 599119, 599123, 599124, 599125, 599126, 599127, 599128, 599132, 599133, 599134, 599135, 599136, 599137, 599138, 599139, 599140, 599141, 599142, 599143, 599144, 599145, 599147, 599148, 599149, 599150, 599151, 599152, 599153, 599154, 599155, 599156, 599157, 599158, 599159, 599178, 599179, 599180, 599181, 599182, 599186, 599187, 599188, 599189, 599190, 599191, 599192, 599193, 599194, 599195, 599196, 599197, 599198, 599199, 599200, 599201, 599202, 599203, 599204, 599205, 599206, 599207, 599208, 599209, 599210, 599211, 599212, 599213, 599214, 599215, 599216, 599217, 599218, 599219, 599220, 599221, 599221, 599222, 599223, 599224, 599225, 599226, 599227, 599228, 599229, 599230, 599231, 599232, 599233, 599234, 599235, 599236, 599241, 599247, 599248, 599249, 599255, 599256, 599257, 599258, 599260, 599261, 599262, 599263, 599264, 599265, 599266, 599267, 599268, 599269, 599270, 599271, 599272, 599273, 599274, 599275, 599276, 599277, 599278, 599279, 599280, 599297, 599299, 599306, 599307, 599308, 599309, 599311, 599312, 599313, 599314, 599315, 599316, 599317, 599318, 599319, 599320, 599321, 599322, 599323, 599324, 599325, 599326, 599327, 599328, 599329, 599330, 599338, 599349, 599353, 599354, 599355, 599356, 599357, 599358, 599359, 599360, 599361, 599362, 599363, 599364, 599369, 599371, 599372, 599373, 599376, 599378, 599379, 599382, 599383, 599384, 599385, 599386, 599387, 599388, 599389, 599390, 599391, 599392, 599393, 599394, 599395, 599396, 599397, 599398, 599399, 599400, 599401, 599402, 599403, 599404, 599405, 599406, 599407, 599408, 599409, 599410, 599412, 599413, 599414, 599415, 599416, 599417, 599418, 599419, 599420, 599421, 599422, 599423, 599424, 599425, 599426, 599433, 599434, 599435, 599436, 599437, 599438, 599439, 599440, 599441, 599442, 599443, 599444, 599445, 599446, 599447, 599448, 599450, 599454, 599455, 599456, 599467, 599468, 599469, 599471, 599472, 599473, 599474, 599475, 599476, 599477, 599478, 599479, 599480, 599481, 599482, 599483, 599484, 599485, 599486, 599487, 599488, 599489, 599490, 599491, 599492, 599493, 599494, 599495, 599496, 599497, 599498, 599499, 599500, 599501, 599502, 599503, 599504, 599505, 599506, 599507, 599508, 599509, 599512, 599515, 599518, 599531, 599541, 599541, 599546, 599547, 599548, 599549, 599550, 599552, 599553, 599554, 599555, 599557, 599558, 599561, 599562, 599563, 599564, 599565, 599566, 599567, 599568, 599569, 599570, 599577, 599578, 599579, 599580, 599581, 599581, 599582, 599584, 599585, 599586, 599587, 599588, 599589, 599590, 599591, 599592, 599593, 599594, 599595, 601321, 601322, 601323, 601325, 601327, 601328, 601329, 601330, 601332, 601333, 601334, 601335, 601336, 601337, 601338, 601339, 601341, 601342, 601343, 601344, 601345, 601346, 601347, 601348, 601349, 601362, 601367, 601368, 601369, 601371, 601372, 601373, 601374, 601375, 601377, 601378, 601380, 601381, 601382, 601383, 601384, 601385, 601386, 601387, and 601388.

[0133] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 50% inhibition of a CFB mRNA, SEQ ID NOs: 12, 30, 33, 36, 37, 84, 85, 86, 87, 88, 89, 90, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 198, 203, 206, 208, 219, 228, 237, 238, 239, 317, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 468, 472, 473, 475, 478, 479, 488, 492, 494, 495, 498, 499, 500, 502, 503, 509, 510, 511, 512, 513, 514, 515, 517, 518, 522, 523, 524, 525, 529, 530, 531, 534, 535, 537, 540, 541, 542, 543, 544, 545, 546, 547, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 563, 564, 565, 569, 570, 572, 573, 577, 588, 589, 590, 591, 592, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 623, 640, 641, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 700, 704, 705, 706, 707, 708, 709, 711, 712, 713, 714, 715, 716, 717, 718, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 758, 759, 760, 761, 762, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 813, 833, 834, 841, 846, 849, 850, 867, and 873.

[0134] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 60% inhibition of a CFB mRNA, ISIS NOs: 516350, 532614, 532635, 532686, 532687, 532688, 532689, 532770, 532800, 532809, 532810, 532811, 532917, 532952, 588512, 588513, 588514, 588515, 588516, 588517, 588518, 588519, 588522, 588523, 588524, 588525, 588527, 588528, 588529, 588530, 588531, 588532, 588533, 588534, 588535, 588536, 588537, 588538, 588539, 588540, 588541, 588542, 588543, 588544, 588545, 588546, 588547, 588548, 588549, 588550, 588551, 588552, 588553, 588554, 588555, 588556, 588557, 588558, 588559, 588560, 588561, 588562, 588563, 588564, 588565, 588566, 588567, 588568, 588569, 588570, 588571, 588572, 588573, 588574, 588575, 588576, 588577, 588636, 588638, 588640, 588664, 588676, 588696, 588698, 588807, 588808, 588814, 588815, 588819, 588820, 588840, 588842, 588846, 588847, 588848, 588849, 588850, 588851, 588852, 588853, 588854, 588855, 588856, 588857, 588858, 588859, 588860, 588861, 588862, 588863, 588864, 588866, 588867, 588868, 588870, 588871, 588872, 588873, 588874, 588875, 588876, 588877, 588878, 588879, 588880, 588881, 588882, 588883, 588884, 598999, 599000, 599001, 599002, 599003, 599004, 599005, 599006, 599007, 599008, 599009, 599010, 599011, 599012, 599013, 599014, 599015, 599019, 599024, 599025, 599026, 599027, 599028, 599029, 599030, 599031, 599032, 599033, 599034, 599035, 599064, 599065, 599071, 599072, 599077, 599078, 599079, 599080, 599083, 599084, 599085, 599086, 599087, 599088, 599089, 599090, 599091, 599092, 599093, 599094, 599095, 599096, 599097, 599125, 599126, 599127, 599133, 599134, 599135, 599136, 599138, 599139, 599140, 599141, 599142, 599148, 599149, 599150, 599151, 599152, 599154, 599155, 599156, 599157, 599158, 599159, 599178, 599179, 599180, 599181, 599187, 599188, 599190, 599192, 599193, 599194, 599195, 599196, 599197, 599198, 599199, 599200, 599201, 599202, 599203, 599204, 599205, 599206, 599207, 599208, 599209, 599210, 599211, 599212, 599213, 599214, 599215, 599216, 599217, 599218, 599219, 599220, 599221, 599222, 599223, 599224, 599225, 599226, 599227, 599228, 599229, 599230, 599231, 599232, 599233, 599234, 599235, 599236, 599247, 599255, 599256, 599257, 599263, 599264, 599265, 599266, 599270, 599271, 599272, 599273, 599274, 599275, 599276, 599277, 599278, 599279, 599280, 599306, 599307, 599308, 599311, 599312, 599313, 599314, 599315, 599316, 599317, 599318, 599319, 599320, 599321, 599322, 599323, 599324, 599325, 599327, 599328, 599329, 599330, 599349, 599353, 599355, 599356, 599357, 599358, 599359, 599360, 599361, 599362, 599363, 599364, 599369, 599371, 599372, 599373, 599376, 599378, 599379, 599382, 599384, 599386, 599387, 599388, 599389, 599390, 599391, 599392, 599393, 599394, 599395, 599396, 599397, 599398, 599399, 599400, 599401, 599402, 599403, 599404, 599405, 599406, 599407, 599408, 599409, 599410, 599412, 599413, 599414, 599415, 599416, 599417, 599418, 599419, 599420, 599421, 599422, 599423, 599424, 599425, 599433, 599434, 599435, 599436, 599437, 599438, 599439, 599440, 599441, 599442, 599443, 599444, 599445, 599446, 599447, 599448, 599456, 599467, 599468, 599471, 599472, 599473, 599474, 599475, 599476, 599477, 599478, 599479, 599480, 599481, 599482, 599483, 599484, 599485, 599486, 599487, 599488, 599489, 599490, 599491, 599492, 599493, 599494, 599495, 599496, 599497, 599498, 599499, 599500, 599501, 599502, 599503, 599504, 599505, 599506, 599507, 599508, 599512, 599531, 599547, 599548, 599549, 599552, 599553, 599554, 599555, 599557, 599558, 599562, 599563, 599564, 599565, 599566, 599567, 599568, 599569, 599570, 599577, 599578, 599579, 599580, 599581, 599582, 599584, 599585, 599586, 599587, 599588, 599589, 599590, 599591, 599592, 599593, 599594, 599595, 601323, 601327, 601329, 601332, 601333, 601333, 601334, 601335, 601336, 601338, 601339, 601341, 601342, 601343, 601344, 601345, 601346, 601347, 601348, 601349, 601368, 601369, 601371, 601372, 601374, 601375, 601377, 601378, 601380, 601381, 601382, 601383, 601384, 601385, 601386, 601387, and 601388.

[0135] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 60% inhibition of a CFB mRNA, SEQ ID NOs: 12, 33, 84, 85, 86, 87, 198, 228, 237, 238, 239, 317, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 472, 473, 513, 514, 515, 531, 537, 541, 542, 543, 544, 545, 546, 547, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 564, 565, 569, 570, 577, 590, 592, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 682, 683, 684, 685, 686, 687, 688, 689, 700, 704, 706, 707, 708, 709, 711, 712, 713, 714, 715, 716, 717, 720, 721, 722, 723, 724, 725, 726, 727, 727, 728, 729, 730, 731, 732, 733, 734, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 758, 759, 760, 761, 767, 768, 770, 772, 773, 774, 775, 775, 776, 776, 777, 777, 778, 779, 780, 781, 782, 783, 783, 784, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 813, 833, 834, 841, 846, 849, and 850.

[0136] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 70% inhibition of a CFB mRNA, ISIS NOs: 516350, 532614, 532686, 532687, 532688, 532770, 532800, 532809, 532810, 532811, 532917, 532952, 588512, 588513, 588514, 588515, 588516, 588517, 588518, 588524, 588529, 588530, 588531, 588532, 588533, 588534, 588535, 588536, 588537, 588538, 588539, 588540, 588541, 588542, 588543, 588544, 588545, 588546, 588547, 588548, 588549, 588550, 588551, 588552, 588553, 588554, 588555, 588556, 588557, 588558, 588559, 588560, 588561, 588562, 588563, 588564, 588565, 588568, 588569, 588570, 588571, 588572, 588573, 588574, 588575, 588577, 588636, 588638, 588640, 588696, 588698, 588807, 588814, 588815, 588819, 588842, 588847, 588848, 588849, 588850, 588851, 588852, 588853, 588856, 588857, 588858, 588859, 588860, 588861, 588862, 588863, 588866, 588867, 588870, 588871, 588872, 588873, 588874, 588875, 588876, 588877, 588878, 588879, 588880, 588881, 588882, 588883, 588884, 599000, 599001, 599003, 599004, 599005, 599008, 599009, 599010, 599011, 599014, 599015, 599024, 599025, 599027, 599028, 599029, 599030, 599031, 599032, 599033, 599034, 599072, 599077, 599080, 599085, 599086, 599087, 599088, 599089, 599090, 599091, 599093, 599094, 599095, 599096, 599097, 599125, 599126, 599134, 599138, 599139, 599148, 599149, 599150, 599151, 599152, 599154, 599155, 599156, 599157, 599158, 599187, 599188, 599193, 599195, 599196, 599197, 599198, 599199, 599200, 599201, 599202, 599203, 599204, 599205, 599206, 599207, 599208, 599210, 599211, 599212, 599213, 599214, 599215, 599216, 599217, 599218, 599219, 599220, 599221, 599222, 599223, 599224, 599225, 599226, 599227, 599228, 599229, 599230, 599231, 599232, 599233, 599234, 599235, 599236, 599266, 599272, 599272, 599273, 599274, 599275, 599277, 599278, 599279, 599280, 599280, 599306, 599311, 599312, 599313, 599314, 599315, 599316, 599317, 599318, 599319, 599320, 599321, 599322, 599323, 599325, 599327, 599328, 599329, 599330, 599355, 599357, 599358, 599359, 599360, 599361, 599362, 599363, 599364, 599369, 599371, 599372, 599373, 599378, 599379, 599382, 599384, 599386, 599387, 599388, 599389, 599390, 599391, 599392, 599393, 599394, 599395, 599396, 599397, 599398, 599399, 599400, 599401, 599402, 599403, 599404, 599405, 599406, 599407, 599408, 599409, 599410, 599413, 599414, 599415, 599416, 599417, 599418, 599419, 599420, 599421, 599422, 599423, 599424, 599433, 599434, 599435, 599436, 599437, 599438, 599439, 599440, 599441, 599442, 599443, 599445, 599446, 599447, 599448, 599472, 599473, 599474, 599475, 599476, 599477, 599478, 599479, 599480, 599481, 599482, 599483, 599484, 599485, 599486, 599487, 599488, 599489, 599490, 599491, 599492, 599493, 599494, 599495, 599496, 599497, 599498, 599499, 599500, 599501, 599502, 599503, 599504, 599505, 599506, 599507, 599508, 599512, 599547, 599548, 599552, 599553, 599554, 599555, 599558, 599562, 599563, 599564, 599566, 599567, 599568, 599569, 599570, 599577, 599578, 599579, 599580, 599581, 599582, 599585, 599586, 599587, 599588, 599589, 599590, 599591, 599592, 599593, 599594, 599595, 601332, 601335, 601341, 601343, 601344, 601345, 601346, 601347, 601348, 601349, 601371, 601372, 601380, 601382, 601383, 601384, 601385, 601386, and 601387.

[0137] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 70% inhibition of a CFB mRNA, SEQ ID NOs: 12, 84, 85, 86, 198, 228, 237, 238, 239, 317, 395, 396, 397, 398, 399, 402, 403, 404, 405, 407, 408, 410, 411, 412, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 464, 465, 472, 473, 513, 514, 515, 541, 542, 543, 544, 545, 546, 547, 549, 550, 551, 552, 553, 554, 555, 556, 557, 564, 565, 569, 592, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 645, 646, 647, 648, 649, 650, 653, 654, 655, 656, 659, 660, 662, 663, 664, 665, 666, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 677, 678, 679, 680, 682, 683, 684, 686, 687, 688, 689, 706, 708, 709, 711, 712, 713, 714, 715, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 767, 768, 773, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 793, 794, 795, 797, 798, 799, 813, 833, 834, 841, 846, 849, 867, and 873.

[0138] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least an 80% inhibition of a CFB mRNA, ISIS NOs: 532686, 532809, 532810, 532811, 532917, 532952, 588512, 588517, 588518, 588533, 588534, 588535, 588536, 588537, 588538, 588539, 588540, 588542, 588543, 588544, 588545, 588546, 588547, 588548, 588549, 588550, 588551, 588552, 588553, 588554, 588555, 588556, 588557, 588558, 588559, 588560, 588561, 588562, 588563, 588564, 588565, 588571, 588638, 588640, 588696, 588698, 588807, 588814, 588849, 588850, 588851, 588853, 588857, 588858, 588859, 588860, 588861, 588862, 588863, 588866, 588867, 588871, 588872, 588873, 588874, 588875, 588876, 588877, 588878, 588879, 588880, 588881, 588882, 588883, 599001, 599024, 599025, 599033, 599086, 599087, 599088, 599089, 599093, 599094, 599095, 599096, 599134, 599139, 599148, 599149, 599151, 599154, 599155, 599156, 599158, 599188, 599195, 599196, 599198, 599201, 599202, 599203, 599204, 599205, 599206, 599207, 599212, 599213, 599215, 599216, 599217, 599218, 599219, 599220, 599221, 599222, 599223, 599224, 599225, 599226, 599227, 599228, 599229, 599230, 599231, 599232, 599233, 599234, 599235, 599236, 599272, 599273, 599275, 599277, 599278, 599279, 599280, 599311, 599313, 599314, 599316, 599317, 599318, 599320, 599321, 599322, 599323, 599327, 599328, 599329, 599330, 599355, 599357, 599358, 599359, 599360, 599361, 599362, 599363, 599364, 599371, 599372, 599373, 599378, 599379, 599382, 599384, 599386, 599387, 599388, 599389, 599390, 599391, 599392, 599393, 599397, 599398, 599399, 599400, 599401, 599403, 599404, 599405, 599407, 599408, 599409, 599410, 599413, 599414, 599415, 599416, 599417, 599418, 599419, 599420, 599421, 599422, 599423, 599424, 599433, 599434, 599435, 599436, 599437, 599438, 599439, 599440, 599441, 599445, 599446, 599447, 599448, 599474, 599476, 599477, 599479, 599481, 599482, 599483, 599485, 599486, 599487, 599488, 599489, 599490, 599491, 599492, 599494, 599495, 599496, 599497, 599498, 599499, 599500, 599502, 599503, 599504, 599505, 599506, 599507, 599508, 599547, 599552, 599553, 599554, 599558, 599563, 599567, 599568, 599569, 599570, 599577, 599578, 599581, 599582, 599585, 599587, 599588, 599590, 599591, 599592, 599593, 599594, 601332, 601344, 601345, 601382, 601383, and 601385.

[0139] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 80% inhibition of a CFB mRNA, SEQ ID NOs: 84, 237, 238, 239, 317, 395, 397, 411, 412, 413, 414, 415, 417, 418, 419, 420, 421, 422, 423, 425, 426, 427, 429, 430, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 472, 473, 514, 515, 542, 543, 544, 545, 546, 547, 550, 551, 552, 553, 554, 555, 556, 557, 564, 595, 599, 600, 601, 602, 603, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 646, 655, 660, 662, 663, 666, 669, 670, 671, 672, 673, 675, 676, 677, 678, 679, 682, 684, 686, 687, 688, 689, 706, 708, 709, 711, 712, 713, 714, 715, 720, 722, 723, 724, 725, 726, 727, 729, 730, 731, 732, 733, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 768, 775, 776, 778, 781, 782, 783, 784, 785, 787, 788, 789, 790, 791, 792, 793, 794, 799, 813, 833, 834, 841, 849, 867, and 873.

[0140] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 90% inhibition of a CFB mRNA, ISIS NOs: 532686, 532811, 532917, 588536, 588537, 588538, 588539, 588544, 588545, 588546, 588548, 588551, 588552, 588553, 588554, 588555, 588556, 588557, 588558, 588559, 588560, 588561, 588562, 588564, 588638, 588640, 588696, 588698, 588849, 588850, 588851, 588860, 588866, 588867, 588872, 588873, 588874, 588876, 588877, 588878, 588879, 588881, 588883, 599149, 599188, 599203, 599206, 599220, 599221, 599222, 599223, 599224, 599225, 599226, 599227, 599228, 599229, 599235, 599236, 599279, 599280, 599314, 599321, 599362, 599378, 599390, 599391, 599398, 599399, 599404, 599413, 599414, 599416, 599419, 599420, 599422, 599435, 599437, 599438, 599441, 599483, 599494, 599508, 599552, 599553, 599554, 599568, 599570, 599577, 599581, 599591, 599592, and 599593.

[0141] In certain embodiments, the following antisense compounds or oligonucleotides target a region of a CFB nucleic acid and effect at least a 90% inhibition of a CFB mRNA, SEQ ID NOs: 84, 238, 239, 317, 412, 413, 420, 421, 426, 434, 436, 437, 438, 439, 440, 442, 443, 444, 445, 446, 448, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 464, 465, 472, 473, 514, 515, 542, 543, 544, 545, 546, 551, 553, 555, 556, 599, 600, 601, 602, 610, 616, 617, 618, 662, 666, 670, 676, 677, 678, 688, 689, 713, 723, 729, 730, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 755, 756, 768, 783, 793, 833, and 867.

[0142] In certain embodiments, a compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleotides 2193-2212, 2195-2210, 2457-2476, 2571-2590, 2584-2603, 2588-2607, 2592-2611, 2594-2613, 2597-2616, 2600-2619, or 2596-2611 of SEQ ID NO: 1.

[0143] In certain embodiments, a compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598.

[0144] In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598.

[0145] In certain embodiments, any of the foregoing compounds or oligonucleotides comprises at least one modified internucleoside linkage, at least one modified sugar, and/or at least one modified nucleobase.

[0146] In certain embodiments, any of the foregoing compounds or oligonucleotides comprises at least one modified sugar. In certain embodiments, at least one modified sugar comprises a 2O-methoxyethyl group. In certain embodiments, at least one modified sugar is a bicyclic sugar, such as a 4CH(CH.sub.3)O-2 group, a 4CH.sub.2O-2 group, or a 4(CH.sub.2).sub.2O-2 group.

[0147] In certain embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage, such as a phosphorothioate internucleoside linkage.

[0148] In certain embodiments, any of the foregoing compounds or oligonucleotides comprises at least one modified nucleobase, such as 5-methylcytosine.

[0149] In certain embodiments, any of the foregoing compounds or oligonucleotides comprises: [0150] a gap segment consisting of linked deoxynucleosides; [0151] a 5 wing segment consisting of linked nucleosides; and [0152] a 3 wing segment consisting of linked nucleosides; [0153] wherein the gap segment is positioned between the 5 wing segment and the 3 wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the oligonucleotide consists of 10 to 30 linked nucleosides having a nucleobase sequence comprising the sequence recited in SEQ ID NO: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, or 598.

[0154] In certain embodiments, the modified oligonucleotide has a nucleobase sequence comprising the sequence recited in SEQ ID NO: 198, 228, 237, 440, 444, 448, 450, 453, or 455, wherein the modified oligonucleotide comprises [0155] a gap segment consisting of ten linked deoxynucleosides; [0156] a 5 wing segment consisting of five linked nucleosides: and [0157] a 3 wing segment consisting of five linked nucleosides; [0158] wherein the gap segment is positioned between the 5 wing segment and the 3 wing segment, wherein each nucleoside of each wing segment comprises a 2O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine.

[0159] In certain embodiments, a compound comprises or consists of a single-stranded modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 198, 228, 237, 440, 444, 448, 450, 453, or 455, wherein the oligonucleotide comprises: [0160] a gap segment consisting of ten linked deoxynucleosides; [0161] a 5 wing segment consisting of five linked nucleosides; and [0162] a 3 wing segment consisting of five linked nucleosides; [0163] wherein the gap segment is positioned between the 5 wing segment and the 3 wing segment, wherein each nucleoside of each wing segment comprises a 2O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage: and wherein each cytosine is a 5-methylcytosine.

[0164] In certain embodiments, a compound comprises ISIS 588540. In certain embodiments, a compound consists of ISIS 588540. In certain embodiments, ISIS 588540 has the following chemical structure:

[0165] In certain embodiments, a compound comprises or consists of a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 549, wherein the modified oligonucleotide comprises [0166] a gap segment consisting of ten linked deoxynucleosides; [0167] a 5 wing segment consisting of three linked nucleosides; and [0168] a 3 wing segment consisting of three linked nucleosides; [0169] wherein the gap segment is positioned between the 5 wing segment and the 3 wing segment; wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.

[0170] In certain embodiments, a compound comprises or consists of a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence comprising the sequence recited in SEQ ID NO: 598, wherein the modified oligonucleotide comprises [0171] a gap segment consisting of ten linked deoxynucleosides; [0172] a 5 wing segment consisting of three linked nucleosides; and [0173] a 3 wing segment consisting of three linked nucleosides; [0174] wherein the gap segment is positioned between the 5 wing segment and the 3 wing segment: wherein the 5 wing segment comprises a 2O-methoxyethyl sugar, 2O-methoxyethyl sugar, and cEt sugar in the 5 to 3 direction: wherein the 3 wing segment comprises a cEt sugar, cEt sugar, and 2O-methoxyethyl sugar in the 5 to 3 direction: wherein each internucleoside linkage is a phosphorothioate linkage: and wherein each cytosine is a 5-methylcytosine.

[0175] In any of the foregoing embodiments, the compound or oligonucleotide can be at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% complementary to a nucleic acid encoding CFB.

[0176] In any of the foregoing embodiments, the compound or oligonucleotide can be single-stranded.

[0177] In certain embodiments, the compounds or compositions as described herein are efficacious by virtue of having at least one of an in vitro IC.sub.50 of less than 250 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 65 nM, less than 60 nM, less than 55 nM, less than 50 nM, less than 45 nM, less than 40 nM, less than 35 nM, less than 30 nM, less than 25 nM, or less than 20 nM.

[0178] In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having at least one of an increase an ALT or AST value of no more than 4 fold, 3 fold, or 2 fold over saline treated animals or an increase in liver, spleen, or kidney weight of no more than 30%, 20%, 15%, 12%, 10%, 5%, or 2%. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase of ALT or AST over saline treated animals. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase in liver, spleen, or kidney weight over saline treated animals.

[0179] Certain embodiments provide a composition comprising the compound of any of the aforementioned embodiments or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. In certain embodiments, the composition has a viscosity less than about 40 centipoise (cP), less than about 30 centipose (cP), less than about 20 centipose (cP), less than about 15 centipose (cP), or less than about 10 centipose (cP). In certain embodiments, the composition having any of the aforementioned viscosities comprises a compound provided herein at a concentration of about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, or about 300 mg/mL. In certain embodiments, the composition having any of the aforementioned viscosities and/or compound concentrations has a temperature of room temperature or about 20? C., about 21? C., about 22? C., about 23? C., about 24? C., about 25? C., about 26? C., about 27? C., about 28? C., about 29? C., or about 30? C.

[0180] In certain embodiments, a method of treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject comprises administering to the subject a specific inhibitor of Complement Factor B (CFB), thereby treating, preventing, or ameliorating the disease. In certain embodiments, the complement alternative pathway is activated greater than normal. In certain embodiments, the CFB specific inhibitor is an antisense compound targeted to CFB, such as an antisense oligonucleotide targeted to CFB. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 588540, which has the following chemical structure:

[0181] In certain embodiments, the disease is macular degeneration, such as age related macular degeneration (AMD), which can be wet AMD or dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, the disease is a kidney disease such as lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof.

[0182] In certain embodiments, a method of treating, preventing, or ameliorating macular degeneration, such as age-related macular degeneration (AMD) in a subject comprises administering to the subject a CFB specific inhibitor, thereby treating, preventing, or ameliorating AMD, such as wet AMD and dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. Geographic Atrophy is considered an advanced form of dry AMD involving degeneration of the retina. In certain embodiments, the subject has a complement alternative pathway that is activated greater than normal. In certain embodiments, administering the antisense compound reduces or inhibits accumulation of ocular C3 levels, such as C3 protein levels. In certain embodiments, administering the antisense compound reduces the level of ocular C3 deposits or inhibits accumulation of ocular C3 deposits. In certain embodiments, the CFB specific inhibitor is an antisense compound targeted to CFB, such as an antisense oligonucleotide targeted to CFB. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430. In certain embodiments, the compound is administered to the subject parenterally.

[0183] In certain embodiments, a method of treating, preventing, or ameliorating a kidney disease associated with dysregulation of the complement alternative pathway in a subject comprises administering to the subject a specific inhibitor of Complement Factor B (CFB), thereby treating, preventing, or ameliorating the kidney disease. In certain embodiments, the complement alternative pathway is activated greater than normal. In certain embodiments, the CFB specific inhibitor is an antisense compound targeted to CFB, such as an antisense oligonucleotide targeted to CFB. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430. In certain embodiments, the compound is administered to the subject parenterally. In certain embodiments, the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD). C3 glomerulonephritis (C3GN). CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof. In certain embodiments, the kidney disease is associated with C3 deposits, such as C3 deposits in the glomerulus. In certain embodiments, the kidney disease is associated with lower than normal circulating C3 levels, such as serum or plasma C3 levels. In certain embodiments, administering the compound reduces or inhibits accumulation of C3 levels in the kidney, such as C3 protein levels. In certain embodiments, administering the compound reduces the level of kidney C3 deposits or inhibits accumulation of kidney C3 deposits, such as C3 levels in the glomerulus. In certain embodiments, the subject is identified as having or at risk of having a disease associated with dysregulation of the complement alternative pathway, for example by detecting complement levels or membrane-attack complex levels in the subject's blood and/or performing a genetic test for gene mutations of complement factors associated with the disease.

[0184] In certain embodiments, a method of inhibiting expression of Complement Factor B (CFB) in a subject having, or at risk of having, a disease associated with dysregulation of the complement alternative pathway comprises administering a Complement Factor B (CFB) specific inhibitor to the subject, thereby inhibiting expression of CFB in the subject. In certain embodiments, administering the inhibitor inhibits expression of CFB in the eye. In certain embodiments, the subject has, or is at risk of having, age related macular degeneration (AMD), such as wet AMD and dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, administering the inhibitor inhibits expression of CFB in the kidney, such as in the glomerulus. In certain embodiments, the subject has, or is at risk of having, lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD). C3 glomerulonephritis (C3GN). CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430. In certain embodiments, the compound is administered to the subject parenterally.

[0185] In certain embodiments, a method of reducing or inhibiting accumulation of C3 deposits in the eye of a subject having, or at risk of having, a disease associated with dysregulation of the complement alternative pathway comprises administering a Complement Factor B (CFB) specific inhibitor to the subject, thereby reducing or inhibiting accumulation of C3 deposits in the eye of the subject. In certain embodiments, the subject has, or is at risk of having, age related macular degeneration (AMD), such as wet AMD and dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, the inhibitor is an antisense compound targeted to CFB. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430. In certain embodiments, the compound is administered to the subject parenterally.

[0186] In certain embodiments, a method of reducing or inhibiting accumulation of C3 deposits in the kidney of a subject having, or at risk of having, a disease associated with dysregulation of the complement alternative pathway comprises administering a Complement Factor B (CFB) specific inhibitor to the subject, thereby reducing or inhibiting accumulation of C3 deposits in the kidney of the subject. In certain embodiments, the subject has, or is at risk of having, lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD). C3 glomerulonephritis (C3GN). CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof. In certain embodiments, the inhibitor is an antisense compound targeted to CFB. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. In certain embodiments, the CFB specific inhibitor is a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430. In certain embodiments, the compound is administered to the subject parenterally.

[0187] Certain embodiments are drawn to a compound or composition described herein for use in therapy. Certain embodiments are drawn to a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808 for use in therapy. Certain embodiments are drawn to a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808 for use in therapy. Certain embodiments are drawn to a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598, for use in therapy. Certain embodiments are drawn to a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430 for use in therapy.

[0188] Certain embodiments are drawn to a compound or composition described herein for use in treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808 for use in treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808 for use in treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598, for use in treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430 for use in treating a disease associated with dysregulation of the complement alternative pathway. In certain embodiments, the complement alternative pathway is activated greater than normal. In certain embodiments, the disease is macular degeneration, such as age related macular degeneration (AMD), which can be wet AMD or dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, the disease is a kidney disease such as lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof.

[0189] Certain embodiments are drawn to a compound comprising or consisting of ISIS 588540, which has the following chemical structure: [0190] , for use in treating a disease associated with dysregulation of the complement alternative pathway. In certain embodiments, the complement alternative pathway is activated greater than normal. In certain embodiments, the disease is macular degeneration, such as age related macular degeneration (AMD), which can be wet AMD or dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, the disease is a kidney disease such as lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof.

[0191] Certain embodiments are drawn to use of a compound or composition described herein for the manufacture of a medicament for treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to use of a compound comprising or consisting of modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 6-808 for the manufacture of a medicament for treating disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to use of a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 6-808 for the manufacture of a medicament for treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to use of a compound comprising or consisting of a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising or consisting of any one of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598, for the manufacture of a medicament for treating a disease associated with dysregulation of the complement alternative pathway. Certain embodiments are drawn to use of a compound comprising or consisting of ISIS 532770, 532800, 532809, 588540, 588544, 588548, 588550, 588553, 588555, 588848, or 594430 for the manufacture of a medicament for treating a disease associated with dysregulation of the complement alternative pathway. In certain embodiments, the complement alternative pathway is activated greater than normal. In certain embodiments, the disease is macular degeneration, such as age related macular degeneration (AMD), which can be wet AMD or dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, the disease is a kidney disease such as lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof.

[0192] Certain embodiments are drawn to use of a compound comprising or consisting of ISIS 588540, which has the following chemical structure: [0193] , for the manufacture of a medicament for treating a disease associated with dysregulation of the complement alternative pathway. In certain embodiments, the complement alternative pathway is activated greater than normal. In certain embodiments, the disease is macular degeneration, such as age related macular degeneration (AMD), which can be wet AMD or dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. In certain embodiments, the disease is a kidney disease such as lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof.

[0194] In any of the foregoing embodiments, the CFB specific inhibitor can be an antisense compound targeted to CFB. In certain embodiments, the antisense compound comprises an antisense oligonucleotide, for example an antisense oligonucleotide consisting of 8 to 80 linked nucleosides, 12 to 30 linked nucleosides, or 20 linked nucleosides. In certain embodiments, the antisense oligonucleotide is at least 80%, 85%, 90%, 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NOs: 1-5. In certain embodiments, the antisense oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar and/or at least one modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage, the modified sugar is a bicyclic sugar or a 2O-methoxyethyl, and the modified nucleobase is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide comprises a gap segment consisting of linked deoxynucleosides; a 5 wing segment consisting of linked nucleosides: and a 3 wing segment consisting of linked nucleosides, wherein the gap segment is positioned immediately adjacent to and between the 5 wing segment and the 3 wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the antisense oligonucleotide is administered parenterally. For example, in certain embodiments the antisense oligonucleotide can be administered through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

Antisense Compounds

[0195] Oligomeric compounds include, but are not limited to, oligonucleotides, oligonucleosides, oligonucleotide analogs, oligonucleotide mimetics, antisense compounds, antisense oligonucleotides, and siRNAs. An oligomeric compound may be antisense to a target nucleic acid, meaning that is is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding.

[0196] In certain embodiments, an antisense compound has a nucleobase sequence that, when written in the 5 to 3 direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted.

[0197] In certain embodiments, an antisense compound is 10 to 30 subunits in length. In certain embodiments, an antisense compound is 12 to 30 subunits in length. In certain embodiments, an antisense compound is 12 to 22 subunits in length. In certain embodiments, an antisense compound is 14 to 30 subunits in length. In certain embodiments, an antisense compound is 14 to 20 subunits in length. In certain embodiments, an antisense compound is 15 to 30 subunits in length. In certain embodiments, an antisense compound is 15 to 20 subunits in length. In certain embodiments, an antisense compound is 16 to 30 subunits in length. In certain embodiments, an antisense compound is 16 to 20 subunits in length. In certain embodiments, an antisense compound is 17 to 30 subunits in length. In certain embodiments, an antisense compound is 17 to 20 subunits in length. In certain embodiments, an antisense compound is 18 to 30 subunits in length. In certain embodiments, an antisense compound is 18 to 21 subunits in length. In certain embodiments, an antisense compound is 18 to 20 subunits in length. In certain embodiments, an antisense compound is 20 to 30 subunits in length. In other words, such antisense compounds are from 12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to 20 subunits, 18 to 21 subunits, 20 to 30 subunits, or 12 to 22 linked subunits, respectively. In certain embodiments, an antisense compound is 14 subunits in length. In certain embodiments, an antisense compound is 16 subunits in length. In certain embodiments, an antisense compound is 17 subunits in length. In certain embodiments, an antisense compound is 18 subunits in length. In certain embodiments, an antisense compound is 19 subunits in length. In certain embodiments, an antisense compound is 20 subunits in length. In other embodiments, the antisense compound is 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. In certain such embodiments, the antisense compounds are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 linked subunits in length, or a range defined by any two of the above values. In some embodiments the antisense compound is an antisense oligonucleotide, and the linked subunits are nucleotides.

[0198] In certain embodiments antisense oligonucleotides may be shortened or truncated. For example, a single subunit may be deleted from the 5 end (5 truncation), or alternatively from the 3 end (3 truncation). A shortened or truncated antisense compound targeted to an CFB nucleic acid may have two subunits deleted from the 5 end, or alternatively may have two subunits deleted from the 3 end, of the antisense compound. Alternatively, the deleted nucleosides may be dispersed throughout the antisense compound, for example, in an antisense compound having one nucleoside deleted from the 5 end and one nucleoside deleted from the 3 end.

[0199] When a single additional subunit is present in a lengthened antisense compound, the additional subunit may be located at the 5 or 3 end of the antisense compound. When two or more additional subunits are present, the added subunits may be adjacent to each other, for example in an antisense compound having two subunits added to the 5 end (5 addition), or alternatively to the 3 end (3 addition), of the antisense compound. Alternatively, the added subunits may be dispersed throughout the antisense compound, for example, in an antisense compound having one subunit added to the 5 end and one subunit added to the 3 end.

[0200] It is possible to increase or decrease the length of an antisense compound, such as an antisense oligonucleotide, and/or introduce mismatch bases without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of antisense oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Antisense oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the antisense oligonucleotides were able to direct specific cleavage of the target mRNA, albeit to a lesser extent than the antisense oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase antisense oligonucleotides, including those with 1 or 3 mismatches.

[0201] Gautschi et al. (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bel-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bel-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo.

[0202] Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358,1988) tested a series of tandem 14 nucleobase antisense oligonucleotides, and a 28 and 42 nucleobase antisense oligonucleotides comprised of the sequence of two or three of the tandem antisense oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase antisense oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase antisense oligonucleotides.

Certain Antisense Compound Motifs and Mechanisms

[0203] In certain embodiments, antisense compounds have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases.

[0204] Chimeric antisense compounds typically contain at least one region modified so as to confer increased resistance to nuclease degradation, increased cellular uptake, increased binding affinity for the target nucleic acid, and/or increased inhibitory activity. A second region of a chimeric antisense compound may confer another desired property e.g., serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of an RNA:DNA duplex.

[0205] Antisense activity may result from any mechanism involving the hybridization of the antisense compound (e.g., oligonucleotide) with a target nucleic acid, wherein the hybridization ultimately results in a biological effect. In certain embodiments, the amount and/or activity of the target nucleic acid is modulated. In certain embodiments, the amount and/or activity of the target nucleic acid is reduced. In certain embodiments, hybridization of the antisense compound to the target nucleic acid ultimately results in target nucleic acid degradation. In certain embodiments, hybridization of the antisense compound to the target nucleic acid does not result in target nucleic acid degradation. In certain such embodiments, the presence of the antisense compound hybridized with the target nucleic acid (occupancy) results in a modulation of antisense activity. In certain embodiments, antisense compounds having a particular chemical motif or pattern of chemical modifications are particularly suited to exploit one or more mechanisms. In certain embodiments, antisense compounds function through more than one mechanism and/or through mechanisms that have not been elucidated. Accordingly, the antisense compounds described herein are not limited by particular mechanism.

[0206] Antisense mechanisms include, without limitation, RNase H mediated antisense; RNAi mechanisms, which utilize the RISC pathway and include, without limitation, siRNA, ssRNA and microRNA mechanisms: and occupancy based mechanisms. Certain antisense compounds may act through more than one such mechanism and/or through additional mechanisms.

RNase H-Mediated Antisense

[0207] In certain embodiments, antisense activity results at least in part from degradation of target RNA by RNase H. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are DNA-like elicit RNase H activity in mammalian cells. Accordingly, antisense compounds comprising at least a portion of DNA or DNA-like nucleosides may activate RNase H, resulting in cleavage of the target nucleic acid. In certain embodiments, antisense compounds that utilize RNase H comprise one or more modified nucleosides. In certain embodiments, such antisense compounds comprise at least one block of 1-8 modified nucleosides. In certain such embodiments, the modified nucleosides do not support RNase H activity. In certain embodiments, such antisense compounds are gapmers, as described herein. In certain such embodiments, the gap of the gapmer comprises DNA nucleosides. In certain such embodiments, the gap of the gapmer comprises DNA-like nucleosides. In certain such embodiments, the gap of the gapmer comprises DNA nucleosides and DNA-like nucleosides.

[0208] Certain antisense compounds having a gapmer motif are considered chimeric antisense compounds. In a gapmer an internal region having a plurality of nucleotides that supports RNaseH cleavage is positioned between external regions having a plurality of nucleotides that are chemically distinct from the nucleosides of the internal region. In the case of an antisense oligonucleotide having a gapmer motif, the gap segment generally serves as the substrate for endonuclease cleavage, while the wing segments comprise modified nucleosides. In certain embodiments, the regions of a gapmer are differentiated by the types of sugar moieties comprising each distinct region. The types of sugar moieties that are used to differentiate the regions of a gapmer may in some embodiments include ?-D-ribonucleosides, ?-D-deoxyribonucleosides, 2-modified nucleosides (such 2-modified nucleosides may include 2-MOE and 2OCH.sub.3, among others), and bicyclic sugar modified nucleosides (such bicyclic sugar modified nucleosides may include those having a constrained ethyl). In certain embodiments, nucleosides in the wings may include several modified sugar moieties, including, for example 2-MOE and bicyclic sugar moieties such as constrained ethyl or LNA. In certain embodiments, wings may include several modified and unmodified sugar moieties. In certain embodiments, wings may include various combinations of 2-MOE nucleosides, bicyclic sugar moieties such as constrained ethyl nucleosides or LNA nucleosides, and 2-deoxynucleosides.

[0209] Each distinct region may comprise uniform sugar moieties, variant, or alternating sugar moieties. The wing-gap-wing motif is frequently described as X-Y-Z, where X represents the length of the 5-wing. Y represents the length of the gap, and Z represents the length of the 3-wing. X and Z may comprise uniform, variant, or alternating sugar moieties. In certain embodiments. X and Y may include one or more 2-deoxynucleosides. Y may comprise 2-deoxynucleosides. As used herein, a gapmer described as XY-Z has a configuration such that the gap is positioned immediately adjacent to each of the 5-wing and the 3 wing. Thus, no intervening nucleotides exist between the 5-wing and gap, or the gap and the 3-wing. Any of the antisense compounds described herein can have a gapmer motif. In certain embodiments, X and Z are the same; in other embodiments they are different. In certain embodiments, Y is between 8 and 15 nucleosides. X, Y, or Z can be any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 or more nucleosides.

[0210] In certain embodiments, the antisense compound targeted to a CFB nucleic acid has a gapmer motif in which the gap consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 linked nucleosides.

[0211] In certain embodiments, the antisense oligonucleotide has a sugar motif described by Formula A as follows: (J).sub.m-(B).sub.n-(J).sub.p-(B).sub.r-(A).sub.t-(D).sub.g-(A).sub.v-(B).sub.w-(J).sub.x-(B).sub.y-(J).sub.z [0212] wherein: [0213] each A is independently a 2-substituted nucleoside; [0214] each B is independently a bicyclic nucleoside; [0215] each J is independently either a 2-substituted nucleoside or a 2-deoxynucleoside; [0216] each D is a 2-deoxynucleoside; [0217] m is 0-4; n is 0-2; p is 0-2; r is 0-2; t is 0-2; v is 0-2; w is 0-4; x is 0-2; y is 0-2; z is 0-4; g is 6-14; provided that: [0218] at least one of m, n, and r is other than 0; [0219] at least one of w and y is other than 0; [0220] the sum of m, n, p, r, and t is from 2 to 5; and [0221] the sum of v, w, x, y, and z is from 2 to 5.

RNAi Compounds

[0222] In certain embodiments, antisense compounds are interfering RNA compounds (RNAi), which include double-stranded RNA compounds (also referred to as short-interfering RNA or siRNA) and single-stranded RNAi compounds (or ssRNA). Such compounds work at least in part through the RISC pathway to degrade and/or sequester a target nucleic acid (thus, include microRNA/microRNA-mimic compounds). In certain embodiments, antisense compounds comprise modifications that make them particularly suited for such mechanisms.

i. ssRNA Compounds

[0223] In certain embodiments, antisense compounds including those particularly suited for use as single-stranded RNAi compounds (ssRNA) comprise a modified 5-terminal end. In certain such embodiments, the 5-terminal end comprises a modified phosphate moiety. In certain embodiments, such modified phosphate is stabilized (e.g., resistant to degradation/cleavage compared to unmodified 5-phosphate). In certain embodiments, such 5-terminal nucleosides stabilize the 5-phosphorous moiety. Certain modified 5-terminal nucleosides may be found in the art, for example in WO/2011/139702.

[0224] In certain embodiments, the 5-nucleoside of an ssRNA compound has Formula IIc:

##STR00002##

wherein: [0225] T.sub.1 is an optionally protected phosphorus moiety; [0226] T.sub.2 is an internucleoside linking group linking the compound of Formula IIc to the oligomeric compound:

[0227] A has one of the formulas:

##STR00003## [0228] Q.sub.1 and Q.sub.2 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.2-C.sub.6 alkynyl or N(R.sub.3)(R.sub.4); [0229] Q.sub.3 is O, S, N(R.sub.5) or C(R.sub.6)(R.sub.7); [0230] each R.sub.3, R.sub.4 R.sub.5, R.sub.6 and R.sub.7 is, independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy; [0231] M.sub.3 is O, S, NR.sub.14, C(R.sub.15)(R.sub.16), C(R.sub.15)(R.sub.16)C(R.sub.17)(R.sub.18), C(R.sub.15)?C(R.sub.17), OC(R.sub.15)(R.sub.16) or OC(R.sub.15)(Bx.sub.2); [0232] R.sub.14 is H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0233] R.sub.15, R.sub.16, R.sub.17 and R.sub.18 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0234] Bx.sub.1 is a heterocyclic base moiety; [0235] or if Bx.sub.2 is present then Bx.sub.2 is a heterocyclic base moiety and Bx.sub.1 is H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0236] J.sub.4, J.sub.5, J.sub.6 and J.sub.7 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0237] or J.sub.4 forms a bridge with one of J.sub.5 or J.sub.7 wherein said bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR.sub.19, C(R.sub.20)(R.sub.21), C(R.sub.20)?C(R.sub.21), C[?C(R.sub.20)(R.sub.21)] and C(?O) and the other two of J.sub.5, J.sub.6 and J.sub.7 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0238] each R.sub.19, R.sub.20 and R.sub.21 is, independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0239] G is H, OH, halogen or O[C(R.sub.5)(R.sub.9)]n-[(C?O).sub.mX.sub.1].sub.jZ; [0240] each R.sub.8 and R.sub.9 is, independently, H, halogen, C.sub.1-C.sub.6 alkyl or substituted C.sub.1-C.sub.6 alkyl; [0241] X.sub.1 is O, S or N(E.sub.1); [0242] Z is H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.2-C.sub.6 alkynyl or N(E.sub.2)(E.sub.3); [0243] E.sub.1, E.sub.2 and E.sub.3 are each, independently, H, C.sub.1-C.sub.6 alkyl or substituted C.sub.1-C.sub.6 alkyl; [0244] n is from 1 to about 6; [0245] m is 0 or 1; [0246] j is 0 or 1; [0247] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ.sub.1, N(J.sub.1)(J.sub.2), =NJ.sub.1, SJ.sub.1, N.sub.3, CN, OC(?X.sub.2)J.sub.1, OC(?X.sub.2)N(J.sub.1)(J.sub.2) and C(?X.sub.2)N(J.sub.1)(J.sub.2); X.sub.2 is O, S or NJ.sub.3; [0248] each J.sub.1, J.sub.2 and J.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl; [0249] when j is 1 then Z is other than halogen or N(E.sub.2)(E.sub.3); and [0250] wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is hybridizable to at least a portion of a target nucleic acid.

[0251] In certain embodiments, M.sub.3 is O, CH?CH, OCH.sub.2 or OC(H)(Bx.sub.2). In certain embodiments, M.sub.3 is O.

[0252] In certain embodiments, J.sub.4, J.sub.5, J.sub.6 and J.sub.7 are each H. In certain embodiments, J.sub.4 forms a bridge with one of J.sub.5 or J.sub.7.

[0253] In certain embodiments, A has one of the formulas:

##STR00004##

wherein: [0254] Q.sub.1 and Q.sub.2 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or substituted C.sub.1-C.sub.6 alkoxy. In certain embodiments, Q.sub.1 and Q.sub.2 are each H. In certain embodiments, Q.sup.1 and Q.sub.2 are each, independently, H or halogen. In certain embodiments, Q.sub.1 and Q.sub.2 is H and the other of Q.sup.1 and Q.sub.2 is F, CH.sub.3 or OCH.sub.3.

[0255] In certain embodiments, T.sub.1 has the formula:

##STR00005##

wherein: [0256] R.sub.a and R.sub.c are each, independently, protected hydroxyl, protected thiol, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, protected amino or substituted amino; and [0257] R.sub.b is O or S. In certain embodiments, R.sub.b is O and R.sub.a and R.sub.c are each, independently, OCH.sub.3, OCH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2.

[0258] In certain embodiments, G is halogen, OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, OCH.sub.2CH.sub.3, O(CH.sub.2).sub.2F, OCH.sub.2CHF.sub.2, OCH.sub.2CF.sub.3, OCH.sub.2CH?CH.sub.2, O(CH.sub.2).sub.2OCH.sub.3, O(CH.sub.2).sub.2SCH.sub.3, O(CH.sub.2).sub.2OCF.sub.3, O(CH.sub.2).sub.3N(R.sub.10)(R.sub.11), O(CH.sub.2).sub.2ON(R.sub.10)(R.sub.11), O(CH.sub.2).sub.2O(CH.sub.2).sub.2N(R.sub.10)(R.sub.11), OCH.sub.2C(?O)N(R.sub.10)(R.sub.11), OCH.sub.2C(?O)N(R.sub.12)(CH.sub.2).sub.2N(R.sub.10)(R.sub.11) or O(CH.sub.2).sub.2N(R.sub.12)C(?NR.sub.13)[N(R.sub.10)(R.sub.11)] wherein R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are each, independently, H or C.sub.1-C.sub.6 alkyl. In certain embodiments, G is halogen, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CF.sub.3, OCH.sub.2CHCH.sub.2, O(CH.sub.2).sub.2OCH.sub.3, O(CH.sub.2).sub.2O(CH.sub.2).sub.2N(CH.sub.3).sub.2, OCH.sub.2C(?O)N(H)CH.sub.3, OCH.sub.2C(?O)N(H)(CH.sub.2).sub.2N(CH.sub.3).sub.2 or OCH.sub.2N(H)C(?NH)NH.sub.2. In certain embodiments, G is F, OCH.sub.3 or O(CH.sub.2).sub.2OCH.sub.3. In certain embodiments, G is O(CH.sub.2).sub.2OCH.sub.3.

[0259] In certain embodiments, the 5-terminal nucleoside has Formula Ile:

##STR00006##

[0260] In certain embodiments, antisense compounds, including those particularly suitable for ssRNA comprise one or more type of modified sugar moieties and/or naturally occurring sugar moieties arranged along an oligonucleotide or region thereof in a defined pattern or sugar modification motif. Such motifs may include any of the sugar modifications discussed herein and/or other known sugar modifications.

[0261] In certain embodiments, the oligonucleotides comprise or consist of a region having uniform sugar modifications. In certain such embodiments, each nucleoside of the region comprises the same RNA-like sugar modification. In certain embodiments, each nucleoside of the region is a 2F nucleoside. In certain embodiments, each nucleoside of the region is a 2OMe nucleoside. In certain embodiments, each nucleoside of the region is a 2-MOE nucleoside. In certain embodiments, each nucleoside of the region is a cEt nucleoside. In certain embodiments, each nucleoside of the region is an LNA nucleoside. In certain embodiments, the uniform region constitutes all or essentially all of the oligonucleotide. In certain embodiments, the region constitutes the entire oligonucleotide except for 1-4 terminal nucleosides.

[0262] In certain embodiments, oligonucleotides comprise one or more regions of alternating sugar modifications, wherein the nucleosides alternate between nucleotides having a sugar modification of a first type and nucleotides having a sugar modification of a second type. In certain embodiments, nucleosides of both types are RNA-like nucleosides. In certain embodiments the alternating nucleosides are selected from: 2OMe, 2-F, 2-MOE, LNA, and cEt. In certain embodiments, the alternating modifications are 2-F and 2-OMe. Such regions may be contiguous or may be interrupted by differently modified nucleosides or conjugated nucleosides.

[0263] In certain embodiments, the alternating region of alternating modifications each consist of a single nucleoside (i.e., the pattern is (AB).sub.xA.sub.y wherein A is a nucleoside having a sugar modification of a first type and B is a nucleoside having a sugar modification of a second type; x is 1-20 and y is 0 or 1). In certain embodiments, one or more alternating regions in an alternating motif includes more than a single nucleoside of a type. For example, oligonucleotides may include one or more regions of any of the following nucleoside motifs: [0264] AABBAA; [0265] ABBABB; [0266] AABAAB; [0267] ABBABAABB; [0268] ABABAA; [0269] AABABAB; [0270] ABABAA; [0271] ABBAABBABABAA; [0272] BABBAABBABABAA or [0273] ABABBAABBABABAA; [0274] wherein A is a nucleoside of a first type and B is a nucleoside of a second type. In certain embodiments, A and B are each selected from 2-F, 2OMe, BNA, and MOE.

[0275] In certain embodiments, oligonucleotides having such an alternating motif also comprise a modified 5 terminal nucleoside, such as those of formula IIc or Ile.

[0276] In certain embodiments, oligonucleotides comprise a region having a 2-2-3 motif. Such regions comprises the following motif:

##STR00007## [0277] wherein: A is a first type of modifed nucleosde; [0278] B and C, are nucleosides that are differently modified than A, however, B and C may have the same or different modifications as one another; [0279] x and y are from 1 to 15.

[0280] In certain embodiments, A is a 2OMe modified nucleoside. In certain embodiments, B and C are both 2-F modified nucleosides. In certain embodiments, A is a 2OMe modified nucleoside and B and C are both 2-F modified nucleosides.

[0281] In certain embodiments, oligonucleosides have the following sugar motif:

##STR00008##

wherein: [0282] Q is a nucleoside comprising a stabilized phosphate moiety. In certain embodiments, Q is a nucleoside having Formula IIc or Ile; [0283] A is a first type of modifed nucleoside; [0284] B is a second type of modified nucleoside; [0285] D is a modified nucleoside comprising a modification different from the nucleoside adjacent to it.

[0286] Thus, if y is 0, then D must be differently modified than B and if y is 1, then D must be differently modified than A. In certain embodiments, D differs from both A and B. [0287] X is 5-15; [0288] Y is 0 or 1; [0289] Z is 0-4.

[0290] In certain embodiments, oligonucleosides have the following sugar motif:

##STR00009##

wherein: [0291] Q is a nucleoside comprising a stabilized phosphate moiety. In certain embodiments, Q is a nucleoside having Formula IIc or Ile; [0292] A is a first type of modifed nucleoside; [0293] D is a modified nucleoside comprising a modification different from A. [0294] X is 11-30; [0295] Z is 0-4.

[0296] In certain embodiments A, B, C, and D in the above motifs are selected from: 2OMe, 2-F, 2-MOE, LNA, and cEt. In certain embodiments, D represents terminal nucleosides. In certain embodiments, such terminal nucleosides are not designed to hybridize to the target nucleic acid (though one or more might hybridize by chance). In certain embodiments, the nucleobase of each D nucleoside is adenine, regardless of the identity of the nucleobase at the corresponding position of the target nucleic acid. In certain embodiments the nucleobase of each D nucleoside is thymine.

[0297] In certain embodiments, antisense compounds, including those particularly suited for use as ssRNA comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate.

[0298] In certain embodiments, the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least one 12 consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3 end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3 end of the oligonucleotide.

[0299] Oligonucleotides having any of the various sugar motifs described herein, may have any linkage motif. For example, the oligonucleotides, including but not limited to those described above, may have a linkage motif selected from non-limiting the table below:

TABLE-US-00001 5 most linkage Central region 3-region PS Alternating PO/PS 6 PS PS Alternating PO/PS 7 PS PS Alternating PO/PS 8 PS
ii. siRNA Compounds

[0300] In certain embodiments, antisense compounds are double-stranded RNAi compounds (siRNA). In such embodiments, one or both strands may comprise any modification motif described above for ssRNA. In certain embodiments, ssRNA compounds may be unmodified RNA. In certain embodiments, siRNA compounds may comprise unmodified RNA nucleosides, but modified internucleoside linkages.

[0301] Several embodiments relate to double-stranded compositions wherein each strand comprises a motif defined by the location of one or more modified or unmodified nucleosides. In certain embodiments, compositions are provided comprising a first and a second oligomeric compound that are fully or at least partially hybridized to form a duplex region and further comprising a region that is complementary to and hybridizes to a nucleic acid target. It is suitable that such a composition comprise a first oligomeric compound that is an antisense strand having full or partial complementarity to a nucleic acid target and a second oligomeric compound that is a sense strand having one or more regions of complementarity to and forming at least one duplex region with the first oligomeric compound.

[0302] The compositions of several embodiments modulate gene expression by hybridizing to a nucleic acid target resulting in loss of its normal function. In certain embodiments, the degradation of the targeted CFB is facilitated by an activated RISC complex that is formed with compositions of the invention.

[0303] Several embodiments are directed to double-stranded compositions wherein one of the strands is useful in, for example, influencing the preferential loading of the opposite strand into the RISC (or cleavage) complex. The compositions are useful for targeting selected nucleic acid molecules and modulating the expression of one or more genes. In some embodiments, the compositions of the present invention hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

[0304] Certain embodiments are drawn to double-stranded compositions wherein both the strands comprises a hemimer motif, a fully modified motif, a positionally modified motif or an alternating motif. Each strand of the compositions of the present invention can be modified to fulfil a particular role in for example the siRNA pathway. Using a different motif in each strand or the same motif with different chemical modifications in each strand permits targeting the antisense strand for the RISC complex while inhibiting the incorporation of the sense strand. Within this model, each strand can be independently modified such that it is enhanced for its particular role. The antisense strand can be modified at the 5-end to enhance its role in one region of the RISC while the 3-end can be modified differentially to enhance its role in a different region of the RISC.

[0305] The double-stranded oligonucleotide molecules can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The double-stranded oligonucleotide molecules can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e. each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double-stranded structure, for example wherein the double-stranded region is about 15 to about 30, e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 base pairs; the antisense strand comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof (e.g., about 15 to about 25 or more nucleotides of the double-stranded oligonucleotide molecule are complementary to the target nucleic acid or a portion thereof). Alternatively, the double-stranded oligonucleotide is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the siRNA are linked by means of a nucleic acid based or non-nucleic acid-based linker(s).

[0306] The double-stranded oligonucleotide can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The double-stranded oligonucleotide can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siRNA molecule capable of mediating RNAi.

[0307] In certain embodiments, the double-stranded oligonucleotide comprises separate sense and antisense sequences or regions, wherein the sense and antisense regions are covalently linked by nucleotide or non-nucleotide linkers molecules as is known in the art, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der waals interactions, hydrophobic interactions, and/or stacking interactions. In certain embodiments, the double-stranded oligonucleotide comprises nucleotide sequence that is complementary to nucleotide sequence of a target gene. In another embodiment, the double-stranded oligonucleotide interacts with nucleotide sequence of a target gene in a manner that causes inhibition of expression of the target gene.

[0308] As used herein, double-stranded oligonucleotides need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non-nucleotides. In certain embodiments, the short interfering nucleic acid molecules lack 2-hydroxy (2OH) containing nucleotides. In certain embodiments short interfering nucleic acids optionally do not include any ribonucleotides (e.g., nucleotides having a 2OH group). Such double-stranded oligonucleotides that do not require the presence of ribonucleotides within the molecule to support RNAi can however have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2OH groups. Optionally, double-stranded oligonucleotides can comprise ribonucleotides at about 5, 10, 20, 30, 40, or 50% of the nucleotide positions. As used herein, the term siRNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics. For example, double-stranded oligonucleotides can be used to epigenetically silence genes at both the post-transcriptional level and the pre-transcriptional level. In a non-limiting example, epigenetic regulation of gene expression by siRNA molecules of the invention can result from siRNA mediated modification of chromatin structure or methylation pattern to alter gene expression (sec. for example. Verdel et al., 2004, Science, 303, 672-676; Pal-Bhadra et al., 2004, Science, 303, 669-672; Allshire, 2002, Science, 297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237).

[0309] It is contemplated that compounds and compositions of several embodiments provided herein can target CFB by a dsRNA-mediated gene silencing or RNAi mechanism, including, e.g., hairpin or stem-loop double-stranded RNA effector molecules in which a single RNA strand with self-complementary sequences is capable of assuming a double-stranded conformation, or duplex dsRNA effector molecules comprising two separate strands of RNA. In various embodiments, the dsRNA consists entirely of ribonucleotides or consists of a mixture of ribonucleotides and deoxynucleotides, such as the RNA/DNA hybrids disclosed, for example, by WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. The dsRNA or dsRNA effector molecule may be a single molecule with a region of self-complementarity such that nucleotides in one segment of the molecule base pair with nucleotides in another segment of the molecule. In various embodiments, a dsRNA that consists of a single molecule consists entirely of ribonucleotides or includes a region of ribonucleotides that is complementary to a region of deoxyribonucleotides. Alternatively, the dsRNA may include two different strands that have a region of complementarity to each other.

[0310] In various embodiments, both strands consist entirely of ribonucleotides, one strand consists entirely of ribonucleotides and one strand consists entirely of deoxyribonucleotides, or one or both strands contain a mixture of ribonucleotides and deoxyribonucleotides. In certain embodiments, the regions of complementarity are at least 70, 80, 90, 95, 98, or 100% complementary to each other and to a target nucleic acid sequence. In certain embodiments, the region of the dsRNA that is present in a double-stranded conformation includes at least 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 75, 100, 200, 500, 1000, 2000 or 5000 nucleotides or includes all of the nucleotides in a cDNA or other target nucleic acid sequence being represented in the dsRNA. In some embodiments, the dsRNA does not contain any single stranded regions, such as single stranded ends, or the dsRNA is a hairpin. In other embodiments, the dsRNA has one or more single stranded regions or overhangs. In certain embodiments. RNA/DNA hybrids include a DNA strand or region that is an antisense strand or region (e.g. has at least 70, 80, 90, 95, 98, or 100% complementarity to a target nucleic acid) and an RNA strand or region that is a sense strand or region (e.g. has at least 70, 80, 90, 95, 98, or 100% identity to a target nucleic acid), and vice versa.

[0311] In various embodiments, the RNA/DNA hybrid is made in vitro using enzymatic or chemical synthetic methods such as those described herein or those described in WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. In other embodiments, a DNA strand synthesized in vitro is complexed with an RNA strand made in vivo or in vitro before, after, or concurrent with the transformation of the DNA strand into the cell. In yet other embodiments, the dsRNA is a single circular nucleic acid containing a sense and an antisense region, or the dsRNA includes a circular nucleic acid and either a second circular nucleic acid or a linear nucleic acid (see, for example, WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999.) Exemplary circular nucleic acids include lariat structures in which the free 5 phosphoryl group of a nucleotide becomes linked to the 2 hydroxyl group of another nucleotide in a loop back fashion.

[0312] In other embodiments, the dsRNA includes one or more modified nucleotides in which the 2 position in the sugar contains a halogen (such as fluorine group) or contains an alkoxy group (such as a methoxy group) which increases the half-life of the dsRNA in vitro or in vivo compared to the corresponding dsRNA in which the corresponding 2 position contains a hydrogen or an hydroxyl group. In yet other embodiments, the dsRNA includes one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The dsRNAs may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the dsRNA contains one or two capped strands, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999.

[0313] In other embodiments, the dsRNA can be any of the at least partially dsRNA molecules disclosed in WO 00/63364, as well as any of the dsRNA molecules described in U.S. Provisional Application 60/399,998; and U.S. Provisional Application 60/419,532, and PCT/US2003/033466, the teaching of which is hereby incorporated by reference. Any of the dsRNAs may be expressed in vitro or in vivo using the methods described herein or standard methods, such as those described in WO 00/63364.

Occupancy

[0314] In certain embodiments, antisense compounds are not expected to result in cleavage or the target nucleic acid via RNase H or to result in cleavage or sequestration through the RISC pathway. In certain such embodiments, antisense activity may result from occupancy, wherein the presence of the hybridized antisense compound disrupts the activity of the target nucleic acid. In certain such embodiments, the antisense compound may be uniformly modified or may comprise a mix of modifications and/or modified and unmodified nucleosides.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

[0315] Nucleotide sequences that encode Complement Factor B (CFB) include, without limitation, the following: GENBANK Accession No. NM_001710.5 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No NW_001116486.1 truncated from nucleotides 536000 to 545000 (incorporated herein as SEQ ID NO: 3), GENBANK Accession No. XM_001113553.2 (incorporated herein as SEQ ID NO: 4), or GENBANK Accession No. NM_008198.2 (incorporated herein as SEQ ID NO: 5).

Hybridization

[0316] In some embodiments, hybridization occurs between an antisense compound disclosed herein and a CFB nucleic acid. The most common mechanism of hybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules.

[0317] Hybridization can occur under varying conditions. Stringent conditions are sequence-dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized.

[0318] Methods of determining whether a sequence is specifically hybridizable to a target nucleic acid are well known in the art. In certain embodiments, the antisense compounds provided herein are specifically hybridizable with a CFB nucleic acid.

Complementarity

[0319] An antisense compound and a target nucleic acid are complementary to each other when a sufficient number of nucleobases of the antisense compound can hydrogen bond with the corresponding nucleobases of the target nucleic acid, such that a desired effect will occur (e.g., antisense inhibition of a target nucleic acid, such as a CFB nucleic acid).

[0320] Non-complementary nucleobases between an antisense compound and a CFB nucleic acid may be tolerated provided that the antisense compound remains able to specifically hybridize to a target nucleic acid. Moreover, an antisense compound may hybridize over one or more segments of a CFB nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).

[0321] In certain embodiments, the antisense compounds provided herein, or a specified portion thereof, are, or are at least, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a CFB nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of an antisense compound with a target nucleic acid can be determined using routine methods.

[0322] For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense compound which is 18 nucleobases in length having four noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present invention. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package. Version 8 for Unix. Genetics Computer Group. University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489).

[0323] In certain embodiments, the antisense compounds provided herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, or specified portion thereof. For example, an antisense compound may be fully complementary to a CFB nucleic acid, or a target region, or a target segment or target sequence thereof. As used herein. fully complementary means each nucleobase of an antisense compound is capable of precise base pairing with the corresponding nucleobases of a target nucleic acid. For example, a 20 nucleobase antisense compound is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the antisense compound. Fully complementary can also be used in reference to a specified portion of the first and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase antisense compound can be fully complementary to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase oligonucleotide is fully complementary to the target sequence if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the antisense compound. At the same time, the entire 30 nucleobase antisense compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the antisense compound are also complementary to the target sequence.

[0324] The location of a non-complementary nucleobase may be at the 5 end or 3 end of the antisense compound. Alternatively, the non-complementary nucleobase or nucleobases may be at an internal position of the antisense compound. When two or more non-complementary nucleobases are present, they may be contiguous (i.e. linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer antisense oligonucleotide.

[0325] In certain embodiments, antisense compounds that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a CFB nucleic acid, or specified portion thereof.

[0326] In certain embodiments, antisense compounds that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a CFB nucleic acid, or specified portion thereof.

[0327] The antisense compounds provided also include those which are complementary to a portion of a target nucleic acid. As used herein, portion refers to a defined number of contiguous (i.e. linked) nucleobases within a region or segment of a target nucleic acid. A portion can also refer to a defined number of contiguous nucleobases of an antisense compound. In certain embodiments, the antisense compounds, are complementary to at least an 8 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 9 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 10 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least an 11 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 13 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 14 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 15 nucleobase portion of a target segment. Also contemplated are antisense compounds that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values.

Identity

[0328] The antisense compounds provided herein may also have a defined percent identity to a particular nucleotide sequence. SEQ ID NO, or compound represented by a specific Isis number, or portion thereof. As used herein, an antisense compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the antisense compounds described herein as well as compounds having non-identical bases relative to the antisense compounds provided herein also are contemplated. The non-identical bases may be adjacent to each other or dispersed throughout the antisense compound. Percent identity of an antisense compound is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared.

[0329] In certain embodiments, the antisense compounds, or portions thereof, are, or are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the antisense compounds or SEQ ID NOs, or a portion thereof, disclosed herein.

[0330] In certain embodiments, a portion of the antisense compound is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

[0331] In certain embodiments, a portion of the antisense oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

Modifications

[0332] A nucleoside is a base-sugar combination. The nucleobase (also known as base) portion of the nucleoside is normally a heterocyclic base moiety. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to the 2, 3 or 5 hydroxyl moiety of the sugar. Oligonucleotides are formed through the covalent linkage of adjacent nucleosides to one another, to form a linear polymeric oligonucleotide. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside linkages of the oligonucleotide.

[0333] Modifications to antisense compounds encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense compounds are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity.

[0334] Chemically modified nucleosides may also be employed to increase the binding affinity of a shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense compounds that have such chemically modified nucleosides.

Modified Internucleoside Linkages

[0335] The naturally occurring internucleoside linkage of RNA and DNA is a 3 to 5 phosphodiester linkage. Antisense compounds having one or more modified, i.e. non-naturally occurring, internucleoside linkages are often selected over antisense compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.

[0336] Oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known.

[0337] In certain embodiments, antisense compounds targeted to a CFB nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage.

Modified Sugar Moieties

[0338] Antisense compounds can optionally contain one or more nucleosides wherein the sugar group has been modified. Such sugar modified nucleosides may impart enhanced nuclease stability, increased binding affinity, or some other beneficial biological property to the antisense compounds. In certain embodiments, nucleosides comprise chemically modified ribofuranose ring moieties. Examples of chemically modified ribofuranose rings include without limitation, addition of substitutent groups (including 5 and 2 substituent groups, bridging of non-geminal ring atoms to form bicyclic nucleic acids (BNA), replacement of the ribosyl ring oxygen atom with S, N(R), or C(R.sub.1)(R.sub.2) (R, R.sub.1 and R.sub.2 are each independently H. C.sub.1-C.sub.12 alkyl or a protecting group) and combinations thereof. Examples of chemically modified sugars include 2-F-5-methyl substituted nucleoside (see PCT International Application WO 2008/101157 Published on Aug. 21, 2008 for other disclosed 5 0,2-bis substituted nucleosides) or replacement of the ribosyl ring oxygen atom with S with further substitution at the 2-position (see published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5-substitution of a BNA (see PCT International Application WO 2007/134181 Published on Nov. 22, 2007 wherein LNA is substituted with for example a 5-methyl or a 5-vinyl group).

[0339] Examples of nucleosides having modified sugar moieties include without limitation nucleosides comprising 5-vinyl, 5-methyl (R or S), 4-S, 2-F, 2OCH.sub.3, 2OCH.sub.2CH.sub.3, 2OCH.sub.2CH.sub.2F and 2O(CH.sub.2).sub.2OCH.sub.3 substituent groups. The substituent at the 2 position can also be selected from allyl, amino, azido, thio, O-allyl. OC.sub.1-C.sub.10 alkyl, OCF.sub.3, OCH.sub.2F, O(CH.sub.2).sub.2SCH.sub.3, O(CH.sub.2).sub.2ON(R.sub.m)(R.sub.n), OCH.sub.2C(?O)N(R.sub.m)(R.sub.n), and OCH.sub.2C(?O)N(R.sub.1)(CH.sub.2).sub.2N(R.sub.m)(R.sub.n), where each R.sub.1, R.sub.m and R.sub.n is, independently, H or substituted or unsubstituted C.sub.1-C.sub.10 alkyl.

[0340] As used herein, bicyclic nucleosides refer to modified nucleosides comprising a bicyclic sugar moiety. Examples of bicyclic nucleosides include without limitation nucleosides comprising a bridge between the 4 and the 2 ribosyl ring atoms. In certain embodiments, antisense compounds provided herein include one or more bicyclic nucleosides comprising a 4 to 2 bridge. Examples of such 4 to 2 bridged bicyclic nucleosides, include but are not limited to one of the formulae: 4(CH.sub.2)O-2 (LNA); 4(CH.sub.2)S-2; 4(CH.sub.2).sub.2O-2 (ENA); 4CH(CH.sub.3)O-2 (also referred to as constrained ethyl or cEt) and 4CH(CH.sub.2OCH.sub.3)O-2 (and analogs thereof see U.S. Pat. No. 7,399,845, issued on Jul. 15, 2008); 4C(CH.sub.3)(CH.sub.3)O-2 (and analogs thereof see published International Application WO/2009/006478, published Jan. 8, 2009); 4CH.sub.2N(OCH.sub.3)-2 (and analogs thereof see published International Application WO/2008/150729, published Dec. 11, 2008); 4CH.sub.2ON(CH.sub.3)-2 (see published U.S. Patent Application US2004-0171570, published September 2. 2004); 4CH.sub.2N(R)O-2, wherein R is H, C.sub.1-C.sub.12 alkyl, or a protecting group (see U.S. Pat. No. 7,427,672, issued on Sep. 23, 2008); 4CH.sub.2C(H)(CH.sub.3)-2 (see Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134); and 4CH.sub.2C(?CH.sub.2)-2 (and analogs thereof see published International Application WO 2008/154401, published on Dec. 8, 2008).

[0341] Further reports related to bicyclic nucleosides can also be found in published literature (see for example: Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A, 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129(26) 8362-8379; Elayadi et al., Curr. Opinion Invest. Drugs. 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; and Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 7,034,133; 7,053,207; 7,399,845; 7,547,684; and 7,696,345; U.S. Patent Publication No. US2008-0039618; US2009-0012281; U.S. Patent Ser. Nos. 60/989,574; 61/026,995; 61/026,998; 61/056,564; 61/086,231; 61/097,787; and 61/099,844; Published PCT International applications WO 1994/014226; WO 2004/106356; WO 2005/021570; WO 2007/134181; WO 2008/150729; WO 2008/154401; and WO 2009/006478. Each of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example ?-L-ribofuranose and ?-D-ribofuranose (see PCT international application PCT/DK98/00393, published on Mar. 25, 1999 as WO 99/14226).

[0342] In certain embodiments, bicyclic sugar moieties of BNA nucleosides include, but are not limited to, compounds having at least one bridge between the 4 and the 2 position of the pentofuranosyl sugar moiety wherein such bridges independently comprises 1 or from 2 to 4 linked groups independently selected from [C(R.sub.a)(R.sub.b)].sub.n, C(R.sub.a)?C(R.sub.b), C(R.sub.a)?N, C(?O), C(?NR.sub.a), C(?S), O, Si(R.sub.a).sub.2, S(?O).sub.x, and N(R.sub.a); [0343] wherein: [0344] x is 0, 1, or 2; [0345] n is 1, 2, 3, or 4; [0346] each R.sub.a and R.sub.b is, independently, H, a protecting group, hydroxyl, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C.sub.5-C.sub.7 alicyclic radical, substituted C.sub.5-C.sub.7 alicyclic radical, halogen, OJ.sub.1, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, COOJ.sub.1, acyl (C(?O)H), substituted acyl, CN, sulfonyl (S(?O).sub.2-J.sub.1), or sulfoxyl (S(?O)-J.sub.1); and [0347] each J.sub.1 and J.sub.2 is, independently, H, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, acyl (C(?O)H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C.sub.1-C.sub.12 aminoalkyl, substituted C.sub.1-C.sub.12 aminoalkyl or a protecting group.

[0348] In certain embodiments, the bridge of a bicyclic sugar moiety is [C(R.sub.a)(R.sub.b)].sub.n, [C(R.sub.a)(R.sub.b)].sub.nO, C(R.sub.aR.sub.b)N(R)O or C(R.sub.aR.sub.b)ON(R). In certain embodiments, the bridge is 4CH.sub.2-2, 4(CH.sub.2).sub.2-2, 4(CH.sub.2).sub.3-2, 4CH.sub.2O-2, 4(CH.sub.2).sub.2O-2, 4CH.sub.2ON(R)-2 and 4CH.sub.2N(R)O-2 wherein each R is, independently, H, a protecting group or C.sub.1-C.sub.12 alkyl.

[0349] In certain embodiments, bicyclic nucleosides are further defined by isomeric configuration. For example, a nucleoside comprising a 4-2 methylene-oxy bridge, may be in the ?-L configuration or in the ?-D configuration. Previously, ?-L-methyleneoxy (4CH.sub.2O-2) BNA's have been incorporated into antisense oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372).

[0350] In certain embodiments, bicyclic nucleosides include, but are not limited to, (A) ?-L-methyleneoxy (4CH.sub.2O-2) BNA, (B) ?-D-methyleneoxy (4CH.sub.2O-2) BNA, (C) ethyleneoxy (4(CH.sub.2).sub.2O-2) BNA, (D) aminooxy (4CH.sub.2ON(R)-2) BNA, (E) oxyamino (4CH.sub.2N(R)O-2) BNA, and (F) methyl(methyleneoxy) (4CH(CH.sub.3)O-2) BNA, (G) methylene-thio (4CH.sub.2S-2) BNA, (H) methylene-amino (4CH.sub.2N(R)-2) BNA, (I) methyl carbocyclic (4CH.sub.2CH(CH.sub.3)-2) BNA, (J) propylene carbocyclic (4(CH.sub.2).sub.3-2) BNA and (K) vinyl BNA as depicted below:

##STR00010## ##STR00011## [0351] wherein Bx is the base moiety and R is independently H, a protecting group, C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 alkoxy.

[0352] In certain embodiments, bicyclic nucleosides are provided having Formula I:

##STR00012##

wherein: [0353] Bx is a heterocyclic base moiety; [0354] -Q.sub.a-Q.sub.b-Q.sub.c-is CH.sub.2N(R.sub.c)CH.sub.2, C(?O)N(R.sub.c)CH.sub.2, CH.sub.2ON(R.sub.c), CH.sub.2N(R.sub.c)O or N(R.sub.c)OCH.sub.2; [0355] R.sub.c is C.sub.1-C.sub.12 alkyl or an amino protecting group; and [0356] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium.

[0357] In certain embodiments, bicyclic nucleosides are provided having Formula II:

##STR00013##

wherein: [0358] Bx is a heterocyclic base moiety; [0359] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; [0360] Z.sub.a is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thio.

[0361] In one embodiment, each of the substituted groups is, independently, mono or poly substituted with substituent groups independently selected from halogen, oxo, hydroxyl, OJ.sub.c, NJ.sub.cJ.sub.d, SJ.sub.c, N.sub.3, OC(?X)J.sub.c, and NJ.sub.eC(?X)NJ.sub.cJ.sub.d, wherein each J.sub.c, J.sub.d and J.sub.c is, independently, H, C.sub.1-C.sub.6 alkyl, or substituted C.sub.1-C.sub.6 alkyl and X is O or NJ.sub.c.

[0362] In certain embodiments, bicyclic nucleosides are provided having Formula III:

##STR00014##

wherein: [0363] Bx is a heterocyclic base moiety; [0364] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; [0365] Z.sub.b is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkynyl or substituted acyl (C(?O)).

[0366] In certain embodiments, bicyclic nucleosides are provided having Formula IV:

##STR00015##

wherein: [0367] Bx is a heterocyclic base moiety; [0368] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; [0369] R.sub.a is C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; [0370] each q.sub.a, q.sub.b, q.sub.c and q.sub.d is, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxyl, substituted C.sub.1-C.sub.6 alkoxyl, acyl, substituted acyl, C.sub.1-C.sub.6 aminoalkyl or substituted C.sub.1-C.sub.6 aminoalkyl;

[0371] In certain embodiments, bicyclic nucleosides are provided having Formula V:

##STR00016##

[0372] wherein: [0373] Bx is a heterocyclic base moiety; [0374] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; [0375] q.sub.a, q.sub.b, q.sub.c and q.sub.r are each, independently, hydrogen, halogen, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.1-C.sub.12 alkoxy, substituted C.sub.1-C.sub.12 alkoxy, OJ.sub.j, SJ.sub.j, SOJ.sub.j, SO.sub.2J.sub.j, NJ.sub.jJ.sub.k, N.sub.3, CN, C(?O)OJ.sub.j, C(?O)NJ.sub.jJ.sub.k, C(?O)J.sub.j, OC(?O)NJ.sub.jJ.sub.k, N(H)C(?NH)NJ.sub.jJ.sub.k, N(H)C(?O)NJ.sub.jJ.sub.k or N(H)C(?S)NJ.sub.jJ.sub.k; [0376] or q.sub.c and q.sub.f together are ?C(q.sub.g)(q.sub.h); [0377] q.sub.g and q.sub.h are each, independently, H, halogen, C.sub.1-C.sub.12 alkyl or substituted C.sub.1-C.sub.12 alkyl.

[0378] The synthesis and preparation of the methyleneoxy (4CH.sub.2O-2) BNA monomers adenine, cytosine, guanine, 5-methyl-cytosine, thymine and uracil, along with their oligomerization, and nucleic acid recognition properties have been described (Koshkin et al., Tetrahedron, 1998, 54, 3607-3630). BNAs and preparation thereof are also described in WO 98/39352 and WO 99/14226.

[0379] Analogs of methyleneoxy (4CH.sub.2O-2) BNA and 2-thio-BNAs, have also been prepared (Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222). Preparation of locked nucleoside analogs comprising oligodeoxyribonucleotide duplexes as substrates for nucleic acid polymerases has also been described (Wengel et al., WO 99/14226). Furthermore, synthesis of 2-amino-BNA, a novel comformationally restricted high-affinity oligonucleotide analog has been described in the art (Singh et al., J. Org. Chem., 1998, 63, 10035-10039). In addition, 2-amino- and 2-methylamino-BNA's have been prepared and the thermal stability of their duplexes with complementary RNA and DNA strands has been previously reported.

[0380] In certain embodiments, bicyclic nucleosides are provided having Formula VI:

##STR00017##

wherein: [0381] Bx is a heterocyclic base moiety; [0382] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; [0383] each q.sub.i, q.sub.j, q.sub.k and q.sub.l is, independently, H, halogen, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.1-C.sub.12 alkoxyl, substituted C.sub.1-C.sub.12 alkoxyl, OJ.sub.j, SJ.sub.j, SOJ.sub.j, SO.sub.2J.sub.j, NJ.sub.jJ.sub.k, N.sub.3, CN, C(?O)OJ.sub.j, C(?O)NJ.sub.jJ.sub.k, C(?O)J.sub.j, OC(?O)NJ.sub.jJ.sub.k, N(H)C(?NH)NJ.sub.jJ.sub.k, N(H)C(?O)NJ.sub.jJ.sub.k or N(H)C(?S)NJ.sub.jJ.sub.k; and [0384] q.sub.i and q.sub.j or q.sub.l and q.sub.k together are ?C(q.sub.g)(q.sub.h), wherein q.sub.g and q.sub.h are each, independently, H, halogen, C.sub.1-C.sub.12 alkyl or substituted C.sub.1-C.sub.12 alkyl.

[0385] One carbocyclic bicyclic nucleoside having a 4(CH.sub.2).sub.3-2 bridge and the alkenyl analog bridge 4-CH?CHCH.sub.2-2 have been described (Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443 and Albaek et al., J. Org. Chem., 2006, 71, 7731-7740). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (Srivastava et al., J. Am. Chem. Soc., 2007, 129(26), 8362-8379).

[0386] As used herein, 4-2 bicyclic nucleoside or 4 to 2 bicyclic nucleoside refers to a bicyclic nucleoside comprising a furanose ring comprising a bridge connecting two carbon atoms of the furanose ring connects the 2 carbon atom and the 4 carbon atom of the sugar ring.

[0387] As used herein, monocylic nucleosides refer to nucleosides comprising modified sugar moieties that are not bicyclic sugar moieties. In certain embodiments, the sugar moiety, or sugar moiety analogue, of a nucleoside may be modified or substituted at any position.

[0388] As used herein, 2-modified sugar means a furanosyl sugar modified at the 2 position. In certain embodiments, such modifications include substituents selected from: a halide, including, but not limited to substituted and unsubstituted alkoxy, substituted and unsubstituted thioalkyl, substituted and unsubstituted amino alkyl, substituted and unsubstituted alkyl, substituted and unsubstituted allyl, and substituted and unsubstituted alkynyl. In certain embodiments, 2 modifications are selected from substituents including, but not limited to: O[(CH.sub.2).sub.nO].sub.mCH.sub.3, O(CH.sub.2).sub.nNH.sub.2, O(CH.sub.2).sub.nCH.sub.3, O(CH.sub.2).sub.nF, O(CH.sub.2).sub.nONH.sub.2, OCH.sub.2C(?O)N(H)CH.sub.3, and O(CH.sub.2).sub.nON[(CH.sub.2).sub.nCH.sub.3].sub.2, where n and m are from 1 to about 10. Other 2-substituent groups can also be selected from: C.sub.1-C.sub.12 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH.sub.3, OCN, C.sub.1, Br, CN, F, CF.sub.3, OCF.sub.3, SOCH.sub.3, SO.sub.2CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving pharmacokinetic properties, or a group for improving the pharmacodynamic properties of an antisense compound, and other substituents having similar properties. In certain embodiments, modifed nucleosides comprise a 2-MOE side chain (Baker et al., J. Biol. Chem., 1997, 272, 11944-12000). Such 2-MOE substitution have been described as having improved binding affinity compared to unmodified nucleosides and to other modified nucleosides, such as 2O-methyl, O-propyl, and O-aminopropyl. Oligonucleotides having the 2-MOE substituent also have been shown to be antisense inhibitors of gene expression with promising features for in vivo use (Martin, Helv. Chim. Acta, 1995, 78, 486-504; Altmann et al., Chimia, 1996, 50, 168-176; Altmann et al., Biochem. Soc. Trans., 1996, 24, 630-637; and Altmann et al., Nucleosides Nucleotides, 1997, 16, 917-926).

[0389] As used herein, a modified tetrahydropyran nucleoside or modified THP nucleoside means a nucleoside having a six-membered tetrahydropyran sugar substituted in for the pentofuranosyl residue in normal nucleosides (a sugar surrogate). Modified THP nucleosides include, but are not limited to, what is referred to in the art as hexitol nucleic acid (HNA), anitol nucleic acid (ANA), manitol nucleic acid (MNA) (see Leumann, Bioorg. Med. Chem., 2002, 10, 841-854) or fluoro HNA (FHNA) having a tetrahydropyran ring system as illustrated below:

##STR00018##

[0390] In certain embodiments, sugar surrogates are selected having Formula VII:

##STR00019##

wherein independently for each of said at least one tetrahydropyran nucleoside analog of Formula VII: [0391] Bx is a heterocyclic base moiety; [0392] T.sub.a and T.sub.b are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound or one of T.sub.a and T.sub.b is an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound and the other of T.sub.a and T.sub.b is H, a hydroxyl protecting group, a linked conjugate group or a 5 or 3-terminal group; [0393] q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; and each of R.sub.1 and R.sub.2 is selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkoxy, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, OC(?X)J.sub.1, OC(?X)NJ.sub.1J.sub.2, NJ.sub.3C(?X)NJ.sub.1J.sub.2 and CN, wherein X is O, S or NJ.sub.1 and each J.sub.1, J.sub.2 and J.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

[0394] In certain embodiments, the modified THP nucleosides of Formula VII are provided wherein q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each H. In certain embodiments, at least one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is other than H. In certain embodiments, at least one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is methyl. In certain embodiments, THP nucleosides of Formula VII are provided wherein one of R.sub.1 and R.sub.2 is fluoro. In certain embodiments, R.sub.1 is fluoro and R.sub.2 is H, R.sub.1 is methoxy and R.sub.2 is H, and R.sub.1 is methoxyethoxy and R.sub.2 is H.

[0395] In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example nucleosides comprising morpholino sugar moieties and their use in oligomeric compounds has been reported (see for example: Braasch et al., Biochemistry, 2002, 41, 4503-4510; and U.S. Pat. Nos. 5,698,685; 5,166,315; 5,185,444; and 5,034,506). As used here, the term morpholino means a sugar surrogate having the following formula:

##STR00020##

[0396] In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as modifed morpholinos.

[0397] Combinations of modifications are also provided without limitation, such as 2-F-5-methyl substituted nucleosides (see PCT International Application WO 2008/101157 published on Aug. 21, 2008 for other disclosed 5, 2-bis substituted nucleosides) and replacement of the ribosyl ring oxygen atom with S and further substitution at the 2-position (see published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5-substitution of a bicyclic nucleic acid (see PCT International Application WO 2007/134181, published on Nov. 22, 2007 wherein a 4CH.sub.2O2 bicyclic nucleoside is further substituted at the 5 position with a 5-methyl or a 5-vinyl group). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (see, e.g., Srivastava et al., J. Am. Chem. Soc. 2007, 129(26), 8362-8379).

[0398] In certain embodiments, antisense compounds comprise one or more modified cyclohexenyl nucleosides, which is a nucleoside having a six-membered cyclohexenyl in place of the pentofuranosyl residue in naturally occurring nucleosides. Modified cyclohexenyl nucleosides include, but are not limited to those described in the art (see for example commonly owned, published PCT Application WO 2010/036696, published on Apr. 10, 2010, Robeyns et al., J. Am. Chem. Soc., 2008, 130(6), 1979-1984; Horv?th et al., Tetrahedron Letters. 2007, 48, 3621-3623; Nauwelaerts et al., J. Am. Chem. Soc., 2007, 129(30), 9340-9348; Gu et al., Nucleosides. Nucleotides & Nucleic Acids, 2005, 24(5-7), 993-998; Nauwelaerts et al., Nucleic Acids Research. 2005, 33(8), 2452-2463; Robeyns et al., Acta Crystallographica. Section F: Structural Biology and Crystallization Communications, 2005, F61(6), 585-586; Gu et al., Tetrahedron, 2004, 60(9), 2111-2123; Gu et al., Oligonucleotides, 2003, 13(6), 479-489; Wang et al., J. Org. Chem., 2003, 68, 4499-4505; Verbeure et al., Nucleic Acids Research, 2001, 29(24), 4941-4947; Wang et al., J. Org. Chem., 2001, 66, 8478-82; Wang et al., Nucleosides, Nucleotides & Nucleic Acids, 2001, 20(4-7), 785-788; Wang et al., J. Am. Chem., 2000, 122, 8595-8602; Published PCT application, WO 06/047842; and Published PCT Application WO 01/049687; the text of each is incorporated by reference herein, in their entirety). Certain modified cyclohexenyl nucleosides have Formula X.

##STR00021## [0399] wherein independently for each of said at least one cyclohexenyl nucleoside analog of Formula X: Bx is a heterocyclic base moiety: [0400] T.sub.3 and T.sub.4 are each, independently, an internucleoside linking group linking the cyclohexenyl nucleoside analog to an antisense compound or one of T.sub.3 and T.sub.4 is an internucleoside linking group linking the tetrahydropyran nucleoside analog to an antisense compound and the other of T.sub.3 and T.sub.4 is H, a hydroxyl protecting group, a linked conjugate group, or a 5- or 3-terminal group; and [0401] q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6, q.sub.7, q.sub.8 and q.sub.9 are each, independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.2-C.sub.6 alkynyl or other sugar substituent group.

[0402] As used herein, 2-modified or 2-substituted refers to a nucleoside comprising a sugar comprising a substituent at the 2 position other than H or OH. 2-modified nucleosides, include, but are not limited to, bicyclic nucleosides wherein the bridge connecting two carbon atoms of the sugar ring connects the 2 carbon and another carbon of the sugar ring; and nucleosides with non-bridging 2 substituents, such as allyl, amino, azido, thio, O-allyl, OC.sub.1-C.sub.10 alkyl, OCF.sub.3, O(CH.sub.2).sub.2OCH.sub.3, 2O(CH.sub.2).sub.2SCH.sub.3, O(CH.sub.2).sub.2ON(R.sub.m)(R.sub.n), or OCH.sub.2C(?O)N(R.sub.m)(R.sub.n), where each R.sub.m and R.sub.n is, independently, H or substituted or unsubstituted C.sub.1-C.sub.10 alkyl. 2-modifed nucleosides may further comprise other modifications, for example at other positions of the sugar and/or at the nucleobase.

[0403] As used herein, 2-F refers to a nucleoside comprising a sugar comprising a fluoro group at the 2 position of the sugar ring.

[0404] As used herein, 2OMe or 2OCH.sub.3 or 2O-methyl each refers to a nucleoside comprising a sugar comprising an OCH.sub.3 group at the 2 position of the sugar ring.

[0405] As used herein, MOE or 2-MOE or 2OCH.sub.2CH.sub.2OCH.sub.3 or 2O-methoxyethyl each refers to a nucleoside comprising a sugar comprising a OCH.sub.2CH.sub.2OCH.sub.3 group at the 2 position of the sugar ring.

[0406] As used herein, oligonucleotide refers to a compound comprising a plurality of linked nucleosides. In certain embodiments, one or more of the plurality of nucleosides is modified. In certain embodiments, an oligonucleotide comprises one or more ribonucleosides (RNA) and/or deoxyribonucleosides (DNA).

[0407] Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense compounds (see for example review article: Leumann, Bioorg. Med. Chem., 2002, 10, 841-854). Such ring systems can undergo various additional substitutions to enhance activity.

[0408] Methods for the preparations of modified sugars are well known to those skilled in the art. Some representative U.S. patents that teach the preparation of such modified sugars include without limitation, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,670,633; 5,700,920; 5,792,847 and 6,600,032 and International Application PCT/US2005/019219, filed Jun. 2, 2005 and published as WO 2005/121371 on Dec. 22, 2005, and each of which is herein incorporated by reference in its entirety.

[0409] In nucleotides having modified sugar moieties, the nucleobase moieties (natural, modified or a combination thereof) are maintained for hybridization with an appropriate nucleic acid target.

[0410] In certain embodiments, antisense compounds comprise one or more nucleosides having modified sugar moieties. In certain embodiments, the modified sugar moiety is 2-MOE. In certain embodiments, the 2-MOE modified nucleosides are arranged in a gapmer motif. In certain embodiments, the modified sugar moiety is a bicyclic nucleoside having a (4CH(CH.sub.3)O2) bridging group. In certain embodiments, the (4CH(CH.sub.3)O2) modified nucleosides are arranged throughout the wings of a gapmer motif.

Modified Nucleobases

[0411] Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Such nucleobase modifications can impart nuclease stability, binding affinity or some other beneficial biological property to antisense compounds. Modified nucleobases include synthetic and natural nucleobases such as, for example, 5-methylcytosine (5-me-C). Certain nucleobase substitutions, including 5-methylcytosine substitutions, are particularly useful for increasing the binding affinity of an antisense compound for a target nucleic acid. For example, 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2? C. (Sanghvi. Y. S., Crooke. S. T. and Lebleu. B., eds., Antisense Research and Applications. CRC Press. Boca Raton, 1993. pp. 276-278).

[0412] Additional modified nucleobases include 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (C?CCH.sub.3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.

[0413] Heterocyclic base moieties can also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Nucleobases that are particularly useful for increasing the binding affinity of antisense compounds include 5-substituted pyrimidines, 6-azapyrimidines and N-2. N-6 and 0-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.

[0414] In certain embodiments, antisense compounds targeted to a CFB nucleic acid comprise one or more modified nucleobases. In certain embodiments, shortened or gap-widened antisense oligonucleotides targeted to a CFB nucleic acid comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

Conjugated Antisense Compounds

[0415] Antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides. Typical conjugate groups include cholesterol moieties and lipid moieties. Additional conjugate groups include carbohydrates, phospholipids, biotin, phenazine folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes.

[0416] Antisense compounds can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of antisense compounds to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications protect the antisense compound having terminal nucleic acid from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5-terminus (5-cap), or at the 3-terminus (3-cap), or can be present on both termini. Cap structures are well known in the art and include, for example, inverted deoxy abasic caps. Further 3 and 5-stabilizing groups that can be used to cap one or both ends of an antisense compound to impart nuclease stability include those disclosed in WO 03/004602 published on Jan. 16, 2003.

[0417] In certain embodiments, antisense compounds, including, but not limited to those particularly suited for use as ssRNA, are modified by attachment of one or more conjugate groups. In general, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, cellular distribution, cellular uptake, charge and clearance. Conjugate groups are routinely used in the chemical arts and are linked directly or via an optional conjugate linking moiety or conjugate linking group to a parent compound such as an oligonucleotide. Conjugate groups includes without limitation, intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins and dyes. Certain conjugate groups have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA. 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether. e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937).

[0418] For additional conjugates including those useful for ssRNA and their placement within antisense compounds, see e.g., U.S. Application No. 61/583,963.

In Vitro Testing of Antisense Oligonucleotides

[0419] Described herein are methods for treatment of cells with antisense oligonucleotides, which can be modified appropriately for treatment with other antisense compounds.

[0420] Cells may be treated with antisense oligonucleotides when the cells reach approximately 60-80% confluency in culture.

[0421] One reagent commonly used to introduce antisense oligonucleotides into cultured cells includes the cationic lipid transfection reagent LIPOFECTIN (Invitrogen, Carlsbad, CA). Antisense oligonucleotides may be mixed with LIPOFECTIN in OPTI-MEM 1 (Invitrogen, Carlsbad, CA) to achieve the desired final concentration of antisense oligonucleotide and a LIPOFECTIN concentration that may range from 2 to 12 ?g/mL per 100 nM antisense oligonucleotide.

[0422] Another reagent used to introduce antisense oligonucleotides into cultured cells includes LIPOFECTAMINE (Invitrogen, Carlsbad, CA). Antisense oligonucleotide is mixed with LIPOFECTAMINE in OPTI-MEM 1 reduced serum medium (Invitrogen, Carlsbad, CA) to achieve the desired concentration of antisense oligonucleotide and a LIPOFECTAMINE concentration that may range from 2 to 12 ?g/mL per 100 nM antisense oligonucleotide.

[0423] Another technique used to introduce antisense oligonucleotides into cultured cells includes electroporation.

[0424] Yet another technique used to introduce antisense oligonucleotides into cultured cells includes free uptake of the oligonucleotides by the cells.

[0425] Cells are treated with antisense oligonucleotides by routine methods. Cells may be harvested 16-24 hours after antisense oligonucleotide treatment, at which time RNA or protein levels of target nucleic acids are measured by methods known in the art and described herein. In general, when treatments are performed in multiple replicates, the data are presented as the average of the replicate treatments.

[0426] The concentration of antisense oligonucleotide used varies from cell line to cell line. Methods to determine the optimal antisense oligonucleotide concentration for a particular cell line are well known in the art. Antisense oligonucleotides are typically used at concentrations ranging from 1 nM to 300 nM when transfected with LIPOFECTAMINE. Antisense oligonucleotides are used at higher concentrations ranging from 625 to 20,000 nM when transfected using electroporation.

RNA Isolation

[0427] RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. Methods of RNA isolation are well known in the art. RNA is prepared using methods well known in the art, for example, using the TRIZOL Reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's recommended protocols.

Certain Indications

[0428] Certain embodiments provided herein relate to methods of treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject by administration of a CFB specific inhibitor, such as an antisense compound targeted to CFB.

[0429] Examples of renal diseases associated with dysregulation of the complement alternative pathway treatable, preventable, and/or ameliorable with the methods provided herein include C.sub.3 glomerulopathy, atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD; also known as MPGN Type II or C.sub.3Neph), and CFHR5 nephropathy.

[0430] Additional renal diseases associated with dysregulation of the complement alternative pathway treatable, preventable, and/or ameliorable with the methods provided herein include IgA nephropathy; mesangiocapillary (membranoproliferative) glomerulonephritis (MPGN); autoimmune disorders including lupus nephritis and systemic lupus erythematosus (SLE); infection-induced glomerulonephritis (also known as Postinfectious glomerulonephritis); and renal ischemia-reperfusion injury, for example post-transplant renal ischemia-reperfusion injury.

[0431] Examples of non-renal disorders associated with dysregulation of the complement alternative pathway treatable and/or preventable with the methods provided herein include ocular diseases such as macular degeneration, for example age-related macular degeneration (AMD), including wet AMD and dry AMD, such as Geographic Atrophy; neuromyelitis optica; corneal disease, such as corneal inflammation; autoimmune uveitis; and diabetic retinopathy. It has been reported that complement system is involved in ocular diseases. Jha P, et al., Mol Immunol (2007) 44(16): 3901-3908. Additional examples of non-renal disorders associated with dysregulation of the complement alternative pathway treatable and/or preventable with the methods provided herein include ANCA-assocaited vasculitis, antiphospholipid syndrome (also known as antiphospholipid antibody syndrome (APS)), asthma, rheumatoid arthritis, Myasthenia Gravis, and multiple sclerosis.

[0432] Certain embodiments provided herein relate to methods of treating, preventing, or ameliorating a renal disease associated with dysregulation of the complement alternative pathway in a subject by administration of a CFB specific inhibitor, such as an antisense compound targeted to CFB. In certain embodiments, the renal disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD). C.sub.3 glomerulonephritis (C.sub.3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS), or any combination thereof.

[0433] Certain embodiments provided herein relate to methods of treating, preventing, or ameliorating macular degeneration, such as age-related macular degeneration (AMD), in a subject by administration of a CFB specific inhibitor, such as an antisense compound targeted to CFB. In certain embodiments, the AMD is wet AMD or dry AMD. In certain embodiments, dry AMD can be Geographic Atrophy. Studies have demonstrated the association of complement alternative pathway dysregulation and AMD. Complement components are common constituents of ocular drusen, the extracellular material that accumulates in the macula of AMD patients. Furthermore, it has been reported that CFH and CFB variants account for nearly 75% of AMD cases in northern Europe and North America. It has also been found that a specific CFB polymorphism confers protection against AMD. Patel. N. et al., Eye (2008) 22(6): 768-76. Additionally. CFB homozygous null mice have lower complement pathway activity, exhibit smaller ocular lesions, and choroidal neovascularization (CNV) after laser photocoagulation. Rohrer. B. et al., Invest Ophthalmol Vis Sci. (2009) 50(7):3056-64. Furthermore. CFB siRNA treatment protects mice from laser induced CNV. Bora, N S et al., J Immunol. (2006) 177(3): 1872-8. Studies have also shown that the kidney and eye share developmental pathways and structural features including basement membrane collagen IV protomer composition and vascularity. Savige et al., J Am Soc Nephrol. (2011) 22(8): 1403-15. There is evidence that the complement pathway is involved in renal and ocular diseases. For instance, inherited complement regulatory protein deficiency causes predisposition to atypical hemolytic uremic syndrome and AMD. Richards A et al., Adv Immunol. (2007) 96:141-77. Additionally, chronic kidney disease has been associated with AMD. Nitsch. D. et al., Ophthalmic Epidemiol. (2009) 16(3): 181-6; Choi. J. et al. Ophthalmic Epidemiol. (2011) 18(6):259-63. Dense deposit disease (DDD), a kidney disease associated with dysregulated complement alternative pathway, is characterized by acute nephritic syndrome and ocular drusen. Cruz and Smith, GeneReviews (2007) Jul. 20. Moreover, mice harboring genetic deletion of a component of the complement alternative pathway have coexisting renal and ocular disease phenotypes. It has been reported that CFH homozygous null mice develop DDD and present retinal abnormalities and visual dysfunction. Pickering et al., Nat Genet. (2002) 31(4):424-8. Mouse models of renal diseases associated with dysregulation of the complement alternative pathway are also accepted as models of AMD. Pennesi M E et al., Mol Apects Med (2012) 33:487-509. CFH null mice, for example, are an accepted model for renal diseases, such as DDD, and AMD. Furthermore, it has been reported that AMD is associated with the systemic source of complement factors, which accumulate locally in the eye to drive alternative pathway complement activation. Loyet et al., Invest Ophthalmol Vis Sci. (2012) 53(10):6628-37.

EXAMPLES

Non-Limiting Disclosure and Incorporation by Reference

[0434] While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety.

[0435] It is understood that the sequence set forth in each SEQ ID NO in the examples contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, antisense compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Antisense compounds described by Isis Number (Isis No) indicate a combination of nucleobase sequence and motif.

Example 1: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells by MOE Gapmers

[0436] Antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 4,500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 (forward sequence AGTCTCTGTGGCATGGTTTGG, designated herein as SEQ ID NO: 810; reverse sequence GGGCGAATGACTGAGATCTTG, designated herein as SEQ ID NO: 811; probe sequence TACCGATTACCACAAGCAACCATGGCA, designated herein as SEQ ID NO: 812) was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0437] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as 5-10-5 MOE gapmers. The 5-10-5 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. Each nucleoside in the 5 wing segment and each nucleoside in the 3 wing segment has a 2-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity.

TABLE-US-00002 TABLE1 InhibitionofCFBmRNAby5-10-5MOE gapmerstargetingSEQIDNO:1and2 SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: % NO: NO: 1 1 inhi- 2 2 SEQ ISIS start stop Target bi- start stop ID NO site site Region Sequence tion site site NO: 532608 20 39 Exon1 GCTGAGCTGC 36 1741 1760 6 CAGTCAAGGA 532609 26 45 Exon1 GGCCCCGCTG 16 1747 1766 7 AGCTGCCAGT 532610 45 64 Exon1 CGGAACATCC 11 1766 1785 8 AAGCGGGAGG 532611 51 70 Exon1 CTTTCCCGGA 26 1772 1791 9 ACATCCAAGC 532612 100 119 Exon1 ATCTGTGTTC 25 1821 1840 10 TGGCACCTGC 532613 148 167 Exon1 GTCACATTCC 39 1869 1888 11 CTTCCCCTGC 532614 154 173 Exon1 GACCTGGTCA 71 1875 1894 12 CATTCCCTTC 532615 160 179 Exon1 GACCTAGACC 35 1881 1900 13 TGGTCACATT 532616 166 185 Exon1 ACTCCAGACC 39 1887 1906 14 TAGACCTGGT 532617 172 191 Exon1 GCTGAAACTC 27 1893 1912 15 CAGACCTAGA 532618 178 197 Exon1 GTCCAAGCTG 29 1899 1918 16 AAACTCCAGA 532619 184 203 Exon1 CTCAGTGTCC 21 1905 1924 17 AAGCTGAAAC 532620 246 265 Exon1 AGGAGAGAAG 31 1967 1986 18 CTGGGCCTGG 532621 252 271 Exon1 GAAGGCAGGA 25 1973 1992 19 GAGAAGCTGG 532622 336 355 Exon GTGGTGGTCA 28 n/a n/a 20 1-2 CACCTCCAGA Junc- tion 532623 381 400 Exon2 CCCTCCAGAG 22 2189 2208 21 AGCAGGATCC 532624 387 406 Exon2 TCTACCCCCT 37 2195 2214 22 CCAGAGAGCA 532625 393 412 Exon2 TTGATCTCTA 30 2201 2220 23 CCCCCTCCAG 532626 417 436 Exon2 TGGAGAAGTC 35 2225 2244 24 GGAAGGAGCC 532627 423 442 Exon2 CCCTCTTGGA 37 2231 2250 25 GAAGTCGGAA 532628 429 448 Exon2 GCCTGGCCCT 0 2237 2256 26 CTTGGAGAAG 532629 435 454 Exon2 TCCAGTGCCT 26 2243 2262 27 GGCCCTCTTG 532630 458 477 Exon2 AGAAGCCAGA 30 2266 2285 28 AGGACACACG 532631 464 483 Exon2 ACGGGTAGAA 43 2272 2291 29 GCCAGAAGGA 532632 480 499 Exon2 CGTGTCTGCA 57 2288 2307 30 CAGGGTACGG 532633 513 532 Exon2 AGGGTGCTCC 27 2321 2340 31 AGGACCCCGT 532634 560 579 Exon TTGCTCTGCA 41 n/a n/a 32 2-3 CTCTGCCTTC Junc- tion 532635 600 619 Exon3 TATTCCCCGT 67 2808 2827 33 TCTCGAAGTC 532636 626 645 Exon3 CATTGTAGTA 24 2834 2853 34 GGGAGACCGG 532637 632 651 Exon3 CACTCACATT 49 2840 2859 35 GTAGTAGGGA 532638 638 657 Exon3 TCTCATCACT 50 2846 2865 36 CACATTGTAG 532639 644 663 Exon3 AAGAGATCTC 52 2852 2871 37 ATCACTCACA 532640 650 669 Exon3 AGTGGAAAGA 34 2858 2877 38 GATCTCATCA 532641 656 675 Exon3 CATAGCAGTG 32 2864 2883 39 GAAAGAGATC 532642 662 681 Exon3 AACCGTCATA 45 2870 2889 40 GCAGTGGAAA 532643 668 687 Exon3 GAGTGTAACC 36 2876 2895 41 GTCATAGCAG 532644 674 693 Exon3 CCCGGAGAGT 30 2882 2901 42 GTAACCGTCA 532645 680 699 Exon3 CAGAGCCCCG 27 2888 2907 43 GAGAGTGTAA 532646 686 705 Exon3 GATTGGCAGA 20 2894 2913 44 GCCCCGGAGA 532647 692 711 Exon3 AGGTGCGATT 28 2900 2919 45 GGCAGAGCCC 532648 698 717 Exon3 CTTGGCAGGT 24 2906 2925 46 GCGATTGGCA 532649 704 723 Exon3 CATTCACTTG 28 2912 2931 47 GCAGGTGCGA 532650 729 748 Exon3 ATCGCTGTCT 44 2937 2956 48 GCCCACTCCA 532651 735 754 Exon3 TCACAGATCG 44 2943 2962 49 CTGTCTGCCC 532652 741 760 Exon3 CCGTTGTCAC 27 2949 2968 50 AGATCGCTGT 532653 747 766 Exon CCCGCTCCGT 28 n/a n/a 51 3-4 TGTCACAGAT Junc- tion 532654 753 772 Exon CAGTACCCCG 13 n/a n/a 52 3-4 CTCCGTTGTC Junc- tion 532655 759 778 Exon TTGGAGCAGT 8 n/a n/a 53 3-4 ACCCCGCTCC Junc- tion 532656 789 808 Exon4 ACCTTCCTTG 40 3152 3171 54 TGCCAATGGG 532657 795 814 Exon4 CTGCCCACCT 41 3158 3177 55 TCCTTGTGCC 532658 818 837 Exon4 CGCTGTCTTC 33 3181 3200 56 AAGGCGGTAC 532659 835 854 Exon4 GCTGCAGTGG 32 3198 3217 57 TAGGTGACGC 532660 841 860 Exon4 CCCCCGGCTG 17 3204 3223 58 CAGTGGTAGG 532661 847 866 Exon4 GGTAAGCCCC 28 3210 3229 59 CGGCTGCAGT 532662 853 872 Exon4 ACGCAGGGTA 13 3216 3235 60 AGCCCCCGGC 532663 859 878 Exon4 GGAGCCACGC 33 3222 3241 61 AGGGTAAGCC 532664 866 885 Exon4 GCCGCTGGGA 10 3229 3248 62 GCCACGCAGG 532665 891 910 Exon4 CAAGAGCCAC 17 3254 3273 63 CTTCCTGACA 532666 897 916 Exon4 CCGCTCCAAG 25 3260 3279 64 AGCCACCTTC 532667 903 922 Exon4 TCCGTCCCGC 29 3266 3285 65 TCCAAGAGCC 532668 909 928 Exon4 GAAGGCTCCG 14 3272 3291 66 TCCCGCTCCA 532669 915 934 Exon4 TGGCAGGAAG 18 3278 3297 67 GCTCCGTCCC 532670 921 940 Exon GAGTCTTGGC 20 n/a n/a 68 4-5 AGGAAGGCTC Junc- tion 532671 927 946 Exon ATGAAGGAGT 14 n/a n/a 69 4-5 CTTGGCAGGA Junc- tion 532672 956 975 Exon5 CTTCGGCCAC 45 3539 3558 70 CTCTTGAGGG 532673 962 981 Exon5 GGAAAGCTTC 37 3545 3564 71 GGCCACCTCT 532674 968 987 Exon5 AAGACAGGAA 28 3551 3570 72 AGCTTCGGCC 532675 974 993 Exon5 TCAGGGAAGA 16 3557 3576 73 CAGGAAAGCT 532676 996 1015 Exon5 TCGACTCCTT 31 3579 3598 74 CTATGGTCTC 532677 1033 1052 Exon CTTCTGTTGT 36 n/a n/a 75 5-6 TCCCCTGGGC Junc- tion 532678 1068 1087 Exon6 TTCATGGAGC 19 3752 3771 76 CTGAAGGGTC 532679 1074 1093 Exon6 TAGATGTTCA 24 3758 3777 77 TGGAGCCTGA 532680 1080 1099 Exon6 ACCAGGTAGA 13 3764 3783 78 TGTTCATGGA 532681 1086 1105 Exon6 TCTAGCACCA 20 3770 3789 79 GGTAGATGTT 532682 1092 1111 Exon6 GATCCATCTA 33 3776 3795 80 GCACCAGGTA 532683 1098 1117 Exon6 CTGTCTGATC 44 3782 3801 81 CATCTAGCAC 532684 1104 1123 Exon6 CCAATGCTGT 29 3788 3807 82 CTGATCCATC 532685 1129 1148 Exon6 TTTGGCTCCT 40 3813 3832 83 GTGAAGTTGC

TABLE-US-00003 TABLE2 InhibitionofCFBmRNAby5-10-5MOEgapmers targetingSEQIDNO:1and2 SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: NO: NO: 1 1 % 2 2 SEQ ISIS start stop Target Inhibi- start stop ID No site site region Sequence tion site site NO: 532686 1135 1154 Exon6 ACACTTTTTG 91 3819 3838 84 GCTCCTGTGA 532687 1141 1160 Exon6 GACTAGACAC 77 3825 3844 85 TTTTTGGCTC 532688 1147 1166 Exon6 TAAGTTGACT 70 3831 3850 86 AGACACTTTT 532689 1153 1172 Exon6 CTCAATTAAG 61 3837 3856 87 TTGACTAGAC 532690 1159 1178 Exon CACCTTCTCA 57 3843 3862 88 6-7 ATTAAGTTGA Junc- tion 532691 1165 1184 Exon ACTTGCCACC 56 n/a n/a 89 6-7 TTCTCAATTA Junc- tion 532692 1171 1190 Exon ACCATAACTT 56 n/a n/a 90 6-7 GCCACCTTCT Junc- tion 532693 1177 1196 Exon7 CTTCACACCA 56 4153 4172 91 TAACTTGCCA 532694 1183 1202 Exon7 TCTTGGCTTC 55 4159 4178 92 ACACCATAAC 532695 1208 1227 Exon7 ATGTGGCATA 55 4184 4203 93 TGTCACTAGA 532696 1235 1254 Exon7 CAGACACTTT 55 4211 4230 94 GACCCAAATT 532697 1298 1317 Exon GGTCTTCATA 53 n/a n/a 95 7-8 ATTGATTTCA Junc- tion 532698 1304 1323 Exon ACTTGTGGTC 53 n/a n/a 96 7-8 TTCATAATTG Junc- tion 532699 1310 1329 Exon ACTTCAACTT 52 n/a n/a 97 7-8 GTGGTCTTCA Junc- tion 532700 1316 1335 Exon8 TCCCTGACTT 52 4609 4628 98 CAACTTGTGG 532701 1322 1341 Exon8 TGTTAGTCCC 52 4615 4634 99 TGACTTCAAC 532702 1328 1347 Exon8 TCTTGGTGTT 51 4621 4640 100 AGTCCCTGAC 532703 1349 1368 Exon8 TGTACACTGC 51 4642 4661 101 CTGGAGGGCC 532704 1355 1374 Exon8 TCATGCTGTA 51 4648 4667 102 CACTGCCTGG 532705 1393 1412 Exon8 GTTCCAGCCT 50 4686 4705 103 TCAGGAGGGA 532706 1399 1418 Exon8 GGTGCGGTTC 50 4692 4711 104 CAGCCTTCAG 532707 1405 1424 Exon8 ATGGCGGGTG 50 4698 4717 105 CGGTTCCAGC 532708 1411 1430 Exon8 GATGACATGG 49 4704 4723 106 CGGGTGCGGT 532709 1417 1436 Exon8 GAGGATGATG 49 4710 4729 107 ACATGGCGGG 532710 1443 1462 Exon CCCATGTTGT 48 n/a n/a 108 8-9 GCAATCCATC Junc- tion 532711 1449 1468 Exon9 TCCCCGCCCA 48 5023 5042 109 TGTTGTGCAA 532712 1455 1474 Exon9 ATTGGGTCCC 48 5029 5048 110 CGCCCATGTT 532713 1461 1480 Exon9 ACAGTAATTG 48 5035 5054 111 GGTCCCCGCC 532714 1467 1486 Exon9 TCAATGACAG 47 5041 5060 112 TAATTGGGTC 532715 1473 1492 Exon9 ATCTCATCAA 47 5047 5066 113 TGACAGTAAT 532716 1479 1498 Exon9 TCCCGGATCT 46 5053 5072 114 CATCAATGAC 532717 1533 1552 Exon ACATCCAGAT 46 n/a n/a 115 9-10 AATCCTCCCT Junc- tion 532718 1539 1558 Exon ACATAGACAT 46 n/a n/a 116 9-10 CCAGATAATC Junc- tion 532719 1545 1564 Exon CCAAACACAT 46 n/a n/a 117 9-10 AGACATCCAG Junc- tion 532720 1582 1601 Exon10 AGCATTGATG 46 5231 5250 118 TTCACTTGGT 532721 1588 1607 Exon10 AGCCAAAGCA 45 5237 5256 119 TTGATGTTCA 532722 1594 1613 Exon10 CTTGGAAGCC 45 5243 5262 120 AAAGCATTGA 532723 1600 1619 Exon10 GTCTTTCTTG 45 5249 5268 121 GAAGCCAAAG 532724 1606 1625 Exon10 CTCATTGTCT 44 5255 5274 122 TTCTTGGAAG 532725 1612 1631 Exon10 ATGTTGCTCA 44 5261 5280 123 TTGTCTTTCT 532726 1618 1637 Exon10 GAACACATGT 44 5267 5286 124 TGCTCATTGT 532727 1624 1643 Exon10 GACTTTGAAC 43 5273 5292 125 ACATGTTGCT 532728 1630 1649 Exon10 ATCCTTGACT 43 5279 5298 126 TTGAACACAT 532729 1636 1655 Exon10 TTCCATATCC 43 5285 5304 127 TTGACTTTGA 532730 1642 1661 Exon10 CAGGTTTTCC 42 5291 5310 128 ATATCCTTGA 532731 1686 1705 Exon11 CTCAGAGACT 42 5827 5846 129 GGCTTTCATC 532732 1692 1711 Exon11 CAGAGACTCA 42 5833 5852 130 GAGACTGGCT 516252 1698 1717 Exon11 ATGCCACAGA 42 5839 5858 131 GACTCAGAGA 532733 1704 1723 Exon11 CAAACCATGC 41 5845 5864 132 CACAGAGACT 532734 1710 1729 Exon11 TGTTCCCAAA 41 5851 5870 133 CCATGCCACA 532735 1734 1753 Exon11 TTGTGGTAAT 41 5875 5894 134 CGGTACCCTT 532736 1740 1759 Exon11 GGTTGCTTGT 40 5881 5900 135 GGTAATCGGT 532737 1746 1765 Exon11 TGCCATGGTT 40 5887 5906 136 GCTTGTGGTA 532738 1752 1771 Exon11 TTGGCCTGCC 40 5893 5912 137 ATGGTTGCTT 532739 1758 1777 Exon11 GAGATCTTGG 38 5899 5918 138 CCTGCCATGG 532740 1803 1822 Exon12 ACAGCCCCCA 38 6082 6101 139 TACAGCTCTC 532741 1809 1828 Exon12 GACACCACAG 38 6088 6107 140 CCCCCATACA 532742 1815 1834 Exon12 TACTCAGACA 38 6094 6113 141 CCACAGCCCC 532743 1821 1840 Exon12 ACAAAGTACT 37 6100 6119 142 CAGACACCAC 532744 1827 1846 Exon12 GTCAGCACAA 37 6106 6125 143 AGTACTCAGA 532745 1872 1891 Exon12 TTGATTGAGT 36 6151 6170 144 GTTCCTTGTC 532746 1878 1897 Exon12 CTGACCTTGA 35 6157 6176 145 TTGAGTGTTC 532747 1909 1928 Exon13 TATCTCCAGG 35 6403 6422 146 TCCCGCTTCT 532748 1967 1986 Exon13 GAATTCCTGC 32 6461 6480 147 TTCTTTTTTC 532749 1973 1992 Exon13 ATTCAGGAAT 32 6467 6486 148 TCCTGCTTCT 532750 1979 1998 Exon13 CATAAAATTC 32 6473 6492 149 AGGAATTCCT 532751 1985 2004 Exon13 CATAGTCATA 31 6479 6498 150 AAATTCAGGA 532752 2006 2025 Exon13 TGAGCTTGAT 30 6500 6519 151 CAGGGCAACG 532753 2012 2031 Exon13 TATTCTTGAG 30 6506 6525 152 CTTGATCAGG 532754 2048 2067 Exon GACAAATGGG 30 n/a n/a 153 13-14 CCTGATAGTC Junc- tion 532755 2070 2089 Exon14 GTTGTTCCCT 29 6659 6678 154 CGGTGCAGGG 532756 2076 2095 Exon14 GCTCGAGTTG 28 6665 6684 155 TTCCCTCGGT 532757 2082 2101 Exon14 CTCAAAGCTC 28 6671 6690 156 GAGTTGTTCC 532758 2088 2107 Exon14 GGAAGCCTCA 25 6677 6696 157 AAGCTCGAGT 532759 2094 2113 Exon14 GTTGGAGGAA 23 6683 6702 158 GCCTCAAAGC 532760 2100 2119 Exon14 GTGGTAGTTG 23 6689 6708 159 GAGGAAGCCT 532761 2106 2125 Exon14 TGGCAAGTGG 18 6695 6714 160 TAGTTGGAGG 532762 2112 2131 Exon14 TGTTGCTGGC 14 6701 6720 161 AAGTGGTAGT

TABLE-US-00004 TABLE3 InhibitionofCFBmRNAby 5-10-5MOEgapmerstargetingSEQIDNO:1and2 SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: % NO: NO: 1 1 inhi- 2 2 SEQ ISIS start stop Target bi- start stop ID NO site site Region Sequence tion site site NO: 532812 n/a n/a Exon1 TCCAGCTCAC 19 1593 1612 162 TCCCCTGTTG 532813 n/a n/a Exon1 TAAGGATCCA 40 1599 1618 163 GCTCACTCCC 532814 n/a n/a Exon1 CAGAAATAAG 39 1605 1624 164 GATCCAGCTC 532815 n/a n/a Exon1 AGGGACCAGA 0 1611 1630 165 AATAAGGATC 532816 n/a n/a Exon1 CCACTTAGGG 27 1617 1636 166 ACCAGAAATA 532817 n/a n/a Exon1 TCCAGGACTC 39 1682 1701 167 TCCCCTTCAG 532818 n/a n/a Exon1 AAGTCCCACC 15 1707 1726 168 CTTTGCTGCC 532819 n/a n/a Exon1 CTGCAGAAGT 26 1713 1732 169 CCCACCCTTT 532820 n/a n/a Exon1 CAGAAACTGC 8 1719 1738 170 AGAAGTCCCA 532821 n/a n/a Exon2 AACCTCTGCA 39 2368 2387 171 -Intron CTCTGCCTTC 2 532822 n/a n/a Exon2 CCCTCAAACC 3 2374 2393 172 -Intron TCTGCACTCT 2 532823 n/a n/a Exon2 TCATTGCCCT 19 2380 2399 173 -Intron CAAACCTCTG 2 532824 n/a n/a Intron2 CCACACTCAT 37 2386 2405 174 TGCCCTCAAA 532825 n/a n/a Intron2 CACTGCCCAC 23 2392 2411 175 ACTCATTGCC 532826 n/a n/a Intron2 TTAGGCCACT 15 2398 2417 176 GCCCACACTC 532827 n/a n/a Intron2 CTAGTCCTGA 28 2436 2455 177 CCTTGCTGCC 532828 n/a n/a Intron2 CTCATCCTAG 25 2442 2461 178 TCCTGACCTT 532829 n/a n/a Intron2 CCTAGTCTCA 23 2448 2467 179 TCCTAGTCCT 532830 n/a n/a Intron2 ACCCTGCCTA 30 2454 2473 180 GTCTCATCCT 532831 n/a n/a Intron2 CTTGTCACCC 34 2460 2479 181 TGCCTAGTCT 532832 n/a n/a Intron2 GCCCACCTTG 36 2466 2485 182 TCACCCTGCC 532833 n/a n/a Intron2 CCTAAAACTG 9 2492 2511 183 CTCCTACTCC 532834 n/a n/a Intron4 GAGTCAGAAA 19 3494 3513 184 TGAGGTCAAA 532835 n/a n/a Intron CCCTACTCCC 16 5971 5990 185 11 ATTTCACCTT 532836 n/a n/a Intron8 TGTTGTGCAA 25 5013 5032 186 -Exon TCCTGCAGAA 9 532837 n/a n/a Intron1 AAAGGCTGAT 18 2123 2142 187 GAAGCCTGGC 532838 n/a n/a Intron7 CCTTTGACCA 21 4461 4480 188 CAAAGTGGCC 532839 n/a n/a Intron AGGTACCACC 29 6362 6381 189 12 TCTTTGTGGG 532840 n/a n/a Intron1 TGGTGGTCAC 34 2143 2162 190 -Exon ACCTGAAGAG 2 532763 2133 2152 Exon GCAGGGAGCA 40 n/a n/a 191 14-15 GCTCTTCCTT Junc- tion 532764 2139 2158 Exon15 TCCTGTGCAG 28 6927 6946 192 GGAGCAGCTC 532765 2145 2164 Exon15 TTGATATCCT 41 6933 6952 193 GTGCAGGGAG 532766 2151 2170 Exon15 AGAGCTTTGA 36 6939 6958 194 TATCCTGTGC 532767 2157 2176 Exon15 ACAAACAGAG 33 6945 6964 195 CTTTGATATC 532768 2163 2182 Exon15 TCAGACACAA 41 6951 6970 196 ACAGAGCTTT 532769 2169 2188 Exon15 TCCTCCTCAG 49 6957 6976 197 ACACAAACAG 532770 2193 2212 Exon15 ACCTCCTTCC 61 6981 7000 198 GAGTCAGCTT 532771 2199 2218 Exon15 ATGTAGACCT 39 6987 7006 199 CCTTCCGAGT 532772 2205 2224 Exon15 TTCTTGATGT 30 6993 7012 200 AGACCTCCTT 532773 2211 2230 Exon15 TCCCCATTCT 31 6999 7018 201 TGATGTAGAC 532774 2217 2236 Exon TTCTTATCCC 36 n/a n/a 202 15-16 CATTCTTGAT Junc- tion 532775 2223 2242 Exon CTGCCTTTCT 56 n/a n/a 203 15-16 TATCCCCATT Junc- tion 532776 2229 2248 Exon TCACAGCTGC 33 n/a n/a 204 15-16 CTTTCTTATC Junc- tion 532777 2235 2254 Exon16 TCTCTCTCAC 38 7119 7138 205 AGCTGCCTTT 532778 2241 2260 Exon16 TGAGCATCTC 51 7125 7144 206 TCTCACAGCT 532779 2247 2266 Exon16 GCATATTGAG 39 7131 7150 207 CATCTCTCTC 532780 2267 2286 Exon16 TGACTTTGTC 56 7151 7170 208 ATAGCCTGGG 532781 2273 2292 Exon16 TGTCCTTGAC 36 7157 7176 209 TTTGTCATAG 532782 2309 2328 Exon16 CAGTACAAAG 30 7193 7212 210 GAACCGAGGG 532783 2315 2334 Exon16 CTCCTCCAGT 21 7199 7218 211 ACAAAGGAAC 532784 2321 2340 Exon16 GACTCACTCC 31 7205 7224 212 TCCAGTACAA 532785 2327 2346 Exon16 CATAGGGACT 30 7211 7230 213 CACTCCTCCA 532786 2333 2352 Exon16 GGTCAGCATA 31 7217 7236 214 GGGACTCACT 532787 2352 2371 Exon TCACCTCTGC 42 7236 7255 215 16-17 AAGTATTGGG Junc- tion 532788 2358 2377 Exon CCAGAATCAC 32 n/a n/a 216 16-17 CTCTGCAAGT Junc- tion 532789 2364 2383 Exon GGGCCGCCAG 35 n/a n/a 217 16-17 AATCACCTCT Junc- tion 532790 2382 2401 Exon17 CTCTTGTGAA 33 7347 7366 218 CTATCAAGGG 532791 2388 2407 Exon17 CGACTTCTCT 52 7353 7372 219 TGTGAACTAT 532792 2394 2413 Exon17 ATGAAACGAC 16 7359 7378 220 TTCTCTTGTG 532793 2400 2419 Exon ACTTGAATGA 45 7365 7384 221 16-17 AACGACTTCT Junc- tion 532794 2406 2425 Exon ACACCAACTT 18 n/a n/a 222 16-17 GAATGAAACG Junc- tion 532795 2427 2446 Exon18 TCCACTACTC 30 7662 7681 223 CCCAGCTGAT 532796 2433 2452 Exon18 CAGACATCCA 38 7668 7687 224 CTACTCCCCA 532797 2439 2458 Exon18 TTTTTGCAGA 35 7674 7693 225 CATCCACTAC 532798 2445 2464 Exon18 TTCTGGTTTT 45 7680 7699 226 TGCAGACATC 532799 2451 2470 Exon18 TGCCGCTTCT 47 7686 7705 227 GGTTTTTGCA 532800 2457 2476 Exon18 TGCTTTTGCC 61 7692 7711 228 GCTTCTGGTT 532801 2463 2482 Exon18 GGTACCTGCT 47 7698 7717 229 TTTGCCGCTT 532802 2469 2488 Exon18 TGAGCAGGTA 31 7704 7723 230 CCTGCTTTTG 532803 2517 2536 Exon18 TTCAGCCAGG 41 7752 7771 231 GCAGCACTTG 532804 2523 2542 Exon18 TTCTCCTTCA 44 7758 7777 232 GCCAGGGCAG 532805 2529 2548 Exon18 TGGAGTTTCT 46 7764 7783 233 CCTTCAGCCA 532806 2535 2554 Exon18 TCATCTTGGA 49 7770 7789 234 GTTTCTCCTT 532807 2541 2560 Exon18 AAATCCTCAT 30 7776 7795 235 CTTGGAGTTT 532808 2547 2566 Exon18 AAACCCAAAT 20 7782 7801 236 CCTCATCTTG 532809 2571 2590 Exon18 GTCCAGCAGG 65 7806 7825 237 AAACCCCTTA 532810 2577 2596 Exon18 GCCCCTGTCC 74 7812 7831 238 AGCAGGAAAC 532811 2599 2618 Exon18 AGCTGTTTTA 96 7834 7853 239 ATTCAATCCC

TABLE-US-00005 TABLE4 InhibitionofCFBmRNAby 5-10-5MOEgapmerstargetingSEQIDNO:1and2 SEQ SEQ SEQ SEQ ID ID ID ID % NO:1 NO:1 NO:2 NO:2 inhi- SEQ ISIS start stop Target start stop bi- ID NO site site region Sequence site site tion NO: 532841 n/a n/a Intron AACTTGCCAC 4142 4161 11 240 6- CTGTGGGTGA Exon7 532842 n/a n/a Exon15- TCACCTTATC 7007 7026 16 241 Intron15 CCCATTCTTG 532843 n/a n/a Intron11 TCAACTTTCA 6015 6034 19 242 CAAACCACCA 532844 n/a n/a Intron16 CCGCCAGAAT 7326 7345 33 243 -Exon17 CACCTGCAAG 532845 n/a n/a Intron10 AGGAGGAATG 5431 5450 29 244 AAGAAGGCTT 532846 n/a n/a Intron13 GCCTTTCCTC 6561 6580 26 245 AGGGATCTGG 532847 n/a n/a Intron4 AAATGTCTGG 3477 3496 18 246 GAGTGTCAGG 532848 n/a n/a Intron15 GCCTAGAGTG 7038 7057 20 247 CCTCCTTAGG 532849 n/a n/a Intron17 GGCATCTCCC 7396 7415 16 248 CAGATAGGAA 532850 n/a n/a Intron6 AGGGAGCTAG 3906 3925 14 249 TCCTGGAAGA 532851 n/a n/a Intron1- ACACCTGAAG 2135 2154 6 250 Exon2 AGAAAGGCTG 532852 n/a n/a Intron7 CCCTTTGACC 4462 4481 25 251 ACAAAGTGGC 532853 n/a n/a Intron7 GCCCTCAAGG 4354 4373 26 252 TAGTCTCATG 532854 n/a n/a Intron6 AAGGGAAGGA 3977 3996 18 253 GGACAGAATA 532855 n/a n/a Intron1 AAAGGCCAAG 2099 2118 9 254 GAGGGATGCT 532856 n/a n/a Exon8- AGAGGTCCCT 4736 4755 4 255 Intron8 TCTGACCATC 532857 n/a n/a Intron8 GCTGGGACAG 4749 4768 0 256 GAGAGAGGTC 532858 n/a n/a Intron4 TCAAATGTCT 3479 3498 13 257 GGGAGTGTCA 532859 n/a n/a Intron10 AGAAGGAGAA 5801 5820 20 258 TGTGCTGAAA 532860 n/a n/a Intron17 TGCTGACCAC 7408 7427 20 259 TTGGCATCTC 532861 n/a n/a Intron11 CAACTTTCAC 6014 6033 18 260 AAACCACCAT 532862 n/a n/a Intron10 AGCTCTGTGA 5497 5516 15 261 TTCTAAGGTT 532863 n/a n/a Intron CCACCTGTGG 4136 4155 16 262 6- GTGAGGAGAA Exon7 532864 n/a n/a Exon17- GAGGACTCAC 7373 7392 21 263 Intron17 TTGAATGAAA 532865 n/a n/a Intron6 TGGAATGATC 3916 3935 30 264 AGGGAGCTAG 532866 n/a n/a Intron5 GTCCCTTCTC 3659 3678 26 265 CATTTTCCCC 532867 n/a n/a Intron7 TCAACTTTTT 4497 4516 14 266 AAGTTAATCA 532868 n/a n/a Intron6 GGGTGAGGAG 4128 4147 21 267 AACAAGGCGC 532869 n/a n/a Intron7 CTTCCAAGCC 4553 4572 5 268 ATCTTTTAAC 532870 n/a n/a Exon17- AGGACTCACT 7372 7391 18 269 Intron17 TGAATGAAAC 532871 n/a n/a Intron10 TTCCAGGCAA 5412 5431 15 270 CTAGAGCTTC 532872 n/a n/a Exon1 CAGAGTCCAG 1557 1576 13 271 CCACTGTTTG 532873 n/a n/a Intron17 CCAACCTGCA 7638 7657 23 272 -Exon18 GAGGCAGTGG 532874 n/a n/a Intron16 TGCAAGGAGA 7312 7331 10 273 GGAGAAGCTG 532875 n/a n/a Exon9- CTAGGCAGGT 5120 5139 21 274 Intron9 TACTCACCCA 532876 n/a n/a Intron CACCATAACT 4148 4167 41 275 6- TGCCACCTGT Exon7 532877 n/a n/a Intron12 TAGGTACCAC 6363 6382 27 276 CTCTTTGTGG 532878 n/a n/a Intron11 CTTGACCTCA 5954 5973 13 277 CCTCCCCCAA 532879 n/a n/a Intron12 CCACCTCTTT 6357 6376 33 278 GTGGGCAGCT 532880 n/a n/a Intron11 TTCACAAACC 6009 6028 8 279 ACCATCTCTT 532881 n/a n/a Exon3- TTCTCACCTC 2958 2977 17 280 Intron3 CGTTGTCACA 532882 n/a n/a Intron12 GAAAGTGGGA 6225 6244 19 281 GGTGTTGCCT 532883 n/a n/a Intron1 ACAGCAGGAA 2075 2094 34 282 GGGAAGGTTA 532884 n/a n/a Intron17 CATGCTGACC 7410 7429 18 283 ACTTGGCATC 532885 n/a n/a Exon4- GGTCACCTTG 3286 3305 0 284 Intron4 GCAGGAAGGC 532886 n/a n/a Intron8 GTATAGTGTT 4804 4823 13 285 ACAAGTGGAC 532887 n/a n/a Intron7 GGACTTCCCT 4468 4487 18 286 TTGACCACAA 532888 n/a n/a Intron11 TCACCTTGAC 5958 5977 20 287 CTCACCTCCC 532889 n/a n/a Intron15 TAGAGTGCCT 7035 7054 27 288 CCTTAGGATG 532890 n/a n/a Intron7 TGACTTCAAC 4605 4624 16 289 TTGTGGTCTG 532891 n/a n/a Intron10 CAGAGAAGGA 5804 5823 25 290 GAATGTGCTG 532892 n/a n/a Intron14 AGGGAGCAGC 6919 6938 47 291 -Exon15 TCTTCCTCTG 532893 n/a n/a Intron5- TGTTCCCCTG 3710 3729 24 292 Exon6 GGTGCCAGGA 532894 n/a n/a Intron10 GGCCTGGCTG 5612 5631 15 293 TTTTCAAGCC 532895 n/a n/a Intron10 GACTGGCTTT 5821 5840 25 294 -Exon11 CATCTGGCAG 532896 n/a n/a Intron10 GAAGGCTTTC 5419 5438 19 295 CAGGCAACTA 532897 n/a n/a Exon17- TCACTTGAAT 7367 7386 11 296 Intron17 GAAACGACTT 532898 n/a n/a Intron1 GGCCCCAAAA 2106 2125 5 297 GGCCAAGGAG 532899 n/a n/a Intron16 AATCACCTGC 7319 7338 19 298 -Exon17 AAGGAGAGGA 532900 n/a n/a Intron12 GACCTTCAGT 6183 6202 25 299 TGCATCCTTA 532901 n/a n/a Intron1 TGATGAAGCC 2117 2136 0 300 TGGCCCCAAA 532902 n/a n/a Intron12 TAGAAAGTGG 6227 6246 0 301 GAGGTGTTGC 532903 n/a n/a Intron12 CCCATCCCTG 6295 6314 14 302 ACTGGTCTGG 532904 n/a n/a Intron8 CCATGGGTAT 4810 4829 13 303 AGTGTTACAA 532905 n/a n/a Intron2 GTGTTCTCTT 2586 2605 23 304 GACTTCCAGG 532906 n/a n/a Intron13 GGCCTGCTCC 6597 6616 27 305 TCACCCCAGT 532907 n/a n/a Intron10 GAGGCCTGGC 5614 5633 32 306 TGTTTTCAAG 532908 n/a n/a Exon1 GACTCTCCCC 1677 1696 16 307 TTCAGTACCT 532909 n/a n/a Intron8 CATGGGTATA 4809 4828 10 308 GTGTTACAAG 532910 n/a n/a Intron10 GAAGGAGAAT 5800 5819 0 309 GTGCTGAAAA 532911 n/a n/a Intron7 TCACCTGGTC 4562 4581 0 310 TTCCAAGCCA 532912 n/a n/a Intron17 CTCCCCAGAT 7391 7410 0 311 AGGAAAGGGA 532913 n/a n/a Exon17- GGACTCACTT 7371 7390 0 312 Intron GAATGAAACG 17 532914 n/a n/a Intron16 GGCCGCCAGA 7328 7347 30 313 -Exon17 ATCACCTGCA 532915 n/a n/a Exon17- CTCACTTGAA 7368 7387 22 314 Intron17 TGAAACGACT 532916 n/a n/a Intron13 CTTTCCCAGC 6569 6588 28 315 CTTTCCTCAG 532918 n/a n/a Intron12 AGAAAGTGGG 6226 6245 3 316 AGGTGTTGCC 532917 2604 2623 Exon18 GTCGCAGCTG 7839 7858 90 317 TTTTAATTCA

TABLE-US-00006 TABLE5 InhibitionofCFBmRNAby 5-10-5MOEgapmerstargetingSEQIDNO:1and2 SEQ SEQ SEQ SEQ ID ID ID ID % NO:1 NO:1 NO:2 NO:2 inhi- SEQ ISIS start stop Target start stop bi- ID NO site site region Sequence site site tion NO: 532919 n/a n/a Exon1 CCAGGACTCT 1681 1700 4 318 CCCCTTCAGT 532920 n/a n/a Intron6 AGGGAAGGAG 3976 3995 25 319 GACAGAATAG 532921 n/a n/a Intron4 GAAATGAGGT 3488 3507 30 320 CAAATGTCTG 532922 n/a n/a Intron4 GGAGAGTCAG 3497 3516 25 321 AAATGAGGTC 532923 n/a n/a Intron12 GTAGAAAGTG 6228 6247 26 322 GGAGGTGTTG 532924 n/a n/a Intron10 TAGAAAGATC 5521 5540 24 323 TCTGAAGTGC 532925 n/a n/a Intron13 CTGCTCCTCA 6594 6613 26 324 CCCCAGTCCT 532926 n/a n/a Intron11 CTACTGGGAT 5927 5946 30 325 TCTGTGCTTA 532927 n/a n/a Intron1 CCCAAAAGGC 2103 2122 13 326 CAAGGAGGGA 532928 n/a n/a Intron17 TGACCACTTG 7405 7424 27 327 GCATCTCCCC 532929 n/a n/a Intron16- CCTGCAAGGA 7314 7333 29 328 Exon17 GAGGAGAAGC 532930 n/a n/a Exon16- CTCTCACCTC 7239 7258 44 329 Intron16 TGCAAGTATT 532931 n/a n/a Intron1 CCCCAAAAGG 2104 2123 21 330 CCAAGGAGGG 532932 n/a n/a Intron7 GTCTTCCAAG 4555 4574 20 331 CCATCTTTTA 532933 n/a n/a Intron8 GTTACAAGTG 4797 4816 30 332 GACTTAAGGG 532934 n/a n/a Intron8- CCCATGTTGT 5017 5036 30 333 Exon9 GCAATCCTGC 532935 n/a n/a Intron15 GAGGTGGGAA 7091 7110 17 334 GCATGGAGAA 532936 n/a n/a Intron14 TGCTCCCACC 6874 6893 21 335 ACTGTCATCT 532937 n/a n/a Exon9- AGGCAGGTTA 5118 5137 18 336 Intron9 CTCACCCAGA 532938 n/a n/a Intron11 TACTGGGATT 5926 5945 15 337 CTGTGCTTAC 532939 n/a n/a Intron13 GCCTTTCCCA 6571 6590 27 338 GCCTTTCCTC 532940 n/a n/a Intron8- GTGCAATCCT 5009 5028 21 339 Exon9 GCAGAAGAGA 532941 n/a n/a Intron8 ACAGGAGAGA 4743 4762 20 340 GGTCCCTTCT 532942 n/a n/a Intron10 CCCAAAAGGA 5717 5736 14 341 GAAAGGGAAA 532943 n/a n/a Intron2 AAGCCCAGGG 2557 2576 32 342 TAAATGCTTA 532944 n/a n/a Intron1 GATGAAGCCT 2116 2135 22 343 GGCCCCAAAA 532945 n/a n/a Intron10 TGGCAGAGAA 5807 5826 22 344 GGAGAATGTG 532946 n/a n/a Intron13 TTCCCAGCCT 6567 6586 35 345 TTCCTCAGGG 532947 n/a n/a Intron10 GGCAGAGAAG 5806 5825 30 346 GAGAATGTGC 532948 n/a n/a Intron10 ACAGTGCCAG 5471 5490 25 347 GAAACAAGAA 532949 n/a n/a Exon9- TAGGCAGGTT 5119 5138 22 348 Intron9 ACTCACCCAG 532950 n/a n/a Intron2 TTCTCTTGAC 2583 2602 22 349 TTCCAGGGCT 532951 n/a n/a Intron13 CCTGCTCCTC 6595 6614 16 350 ACCCCAGTCC 532953 n/a n/a Intron7 TCCCACTAAC 4422 4441 14 351 CTCCATTGCC 532954 n/a n/a Intron7 TTCCCTTTGA 4464 4483 16 352 CCACAAAGTG 532955 n/a n/a Intron9 CTGGGTCCTA 5127 5146 30 353 GGCAGGTTAC 532956 n/a n/a Intron10 TCCAGGCAAC 5411 5430 20 354 TAGAGCTTCA 532957 n/a n/a Intron8- GCCCATGTTG 5018 5037 45 355 Exon9 TGCAATCCTG 532958 n/a n/a Intron7 GGTTCCCACT 4425 4444 18 356 AACCTCCATT 532959 n/a n/a Intron3 AGGTAGAGAG 3052 3071 26 357 CAAGAGTTAC 532960 n/a n/a Intron7 CCACTAACCT 4420 4439 10 358 CCATTGCCCA 532961 n/a n/a Intron11 TCACAAACCA 6008 6027 40 359 CCATCTCTTA 532962 n/a n/a Exon9- TACTCACCCA 5110 5129 27 360 Intron9 GATAATCCTC 532963 n/a n/a Intron13 TGCTCCTCAC 6593 6612 24 361 CCCAGTCCTC 532964 n/a n/a Intron15- TCTCACAGCT 7115 7134 25 362 Exon16 GCCTTTCTGT 532965 n/a n/a Exon17- GAAAGGGAGG 7379 7398 11 363 Intron17 ACTCACTTGA 532966 n/a n/a Intron7 CCATCTTTTA 4545 4564 18 364 ACCCCAGAGA 532967 n/a n/a Intron13 TCCTCACCCC 6590 6609 27 365 AGTCCTCCAG 532968 n/a n/a Intron10 CTGGCAGAGA 5808 5827 15 366 AGGAGAATGT 532969 n/a n/a Intron17 TCTCCCCAGA 7392 7411 23 367 TAGGAAAGGG 532970 n/a n/a Intron14 ACTTCAGCTG 6882 6901 18 368 CTCCCACCAC 532971 n/a n/a Intron1 GACAGCAGGA 2076 2095 13 369 AGGGAAGGTT 532972 n/a n/a Intron13- GGAGACAAAT 6640 6659 33 370 Exon14 GGGCCTATAA 532973 n/a n/a Intron14 CTGCTCCCAC 6875 6894 11 371 CACTGTCATC 532974 n/a n/a Intron10 AGGAATGAAG 5428 5447 21 372 AAGGCTTTCC 532975 n/a n/a Intron14 GGGATCTCAT 6741 6760 31 373 CCTTATCCTC 532976 n/a n/a Intron9 GTGCTGGGTC 5130 5149 16 374 CTAGGCAGGT 532977 n/a n/a Intron1 CAAAAGGCCA 2101 2120 14 375 AGGAGGGATG 532978 n/a n/a Intron17 CCATGCTGAC 7411 7430 20 376 CACTTGGCAT 532979 n/a n/a Intron8 GGAGGCTGGG 4753 4772 25 377 ACAGGAGAGA 532980 n/a n/a Intron14- GGAGCAGCTC 6917 6936 36 378 Exon15 TTCCTCTGGA 532981 n/a n/a Exon3- TCTCACCTCC 2957 2976 20 379 Intron3 GTTGTCACAG 532982 n/a n/a Intron13 CAGTCCTCCA 6581 6600 21 380 GCCTTTCCCA 532983 n/a n/a Intron13 AGTCCTCCAG 6580 6599 22 381 CCTTTCCCAG 532984 n/a n/a Intron4- TGAAGGAGTC 3509 3528 12 382 Exon5 TGGGAGAGTC 532985 n/a n/a Intron16- CAGAATCACC 7322 7341 20 383 Exon17 TGCAAGGAGA 532986 n/a n/a Exon17- TAGGAAAGGG 7382 7401 3 384 Intron17 AGGACTCACT 532987 n/a n/a Exon4- ACCTTGGCAG 3282 3301 12 385 Intron4 GAAGGCTCCG 532988 n/a n/a Intron13- GAGACAAATG 6639 6658 15 386 Exon14 GGCCTATAAA 532989 n/a n/a Intron1 CTGAAGAGAA 2131 2150 17 387 AGGCTGATGA 532990 n/a n/a Intron6 AATGATCAGG 3913 3932 30 388 GAGCTAGTCC 532991 n/a n/a Intron17 CTTAGCTGAC 7557 7576 22 389 CTAAAGGAAT 532992 n/a n/a Intron8 TGGGTATAGT 4807 4826 17 390 GTTACAAGTG 532993 n/a n/a Intron1 TGAAGAGAAA 2130 2149 19 391 GGCTGATGAA 532994 n/a n/a Intron8 GTGTTACAAG 4799 4818 25 392 TGGACTTAAG 532995 n/a n/a Intron6 ACCTGTGGGT 4134 4153 24 393 GAGGAGAACA 532996 n/a n/a Exon9- TCACCCAGAT 5107 5126 36 394 Intron9 AATCCTCCCT 532952 2608 2627 Exon18 TGTTGTCGCA 7843 7862 90 395 GCTGTTTTAA

Example 2: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells by MOE Gapmers

[0438] Additional antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 4,500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3460_MGB (forward sequence CGAAGCAGCTCAATGAAATCAA, designated herein as SEQ ID NO: 813; reverse sequence TGCCTGGAGGGCCTTCTT, designated herein as SEQ ID NO: 814; probe sequence AGACCACAAGTTGAAGTC, designated herein as SEQ ID NO: 815) was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0439] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as 5-10-5 MOE gapmers. The 5-10-5 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. Each nucleoside in the 5 wing segment and each nucleoside in the 3 wing segment has a 2-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity.

TABLE-US-00007 TABLE6 InhibitionofCFBmRNAby 5-10-5MOEgapmerstargetingSEQIDNO:1and2 SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: % NO: NO: 1 1 inhi- 2 2 SEQ ISIS start stop Target bi- start stop ID NO site site region Sequence tion site site NO: 532686 1135 1154 Exon6 ACACTTTTTG 48 3819 3838 84 GCTCCTGTGA 532687 1141 1160 Exon6 GACTAGACAC 63 3825 3844 85 TTTTTGGCTC 532688 1147 1166 Exon6 TAAGTTGACT 47 3831 3850 86 AGACACTTTT 532689 1153 1172 Exon6 CTCAATTAAG 57 3837 3856 87 TTGACTAGAC 532690 1159 1178 Exon CACCTTCTCA 49 3843 3862 88 6-7 ATTAAGTTGA Junc- tion 532691 1165 1184 Exon ACTTGCCACC 33 n/a n/a 89 6-7 TTCTCAATTA Junc- tion 532692 1171 1190 Exon ACCATAACTT 67 n/a n/a 90 6-7 GCCACCTTCT Junc- tion 532693 1177 1196 Exon7 CTTCACACCA 56 4153 4172 91 TAACTTGCCA 532694 1183 1202 Exon7 TCTTGGCTTC 50 4159 4178 92 ACACCATAAC 532695 1208 1227 Exon7 ATGTGGCATA 53 4184 4203 93 TGTCACTAGA 532696 1235 1254 Exon7 CAGACACTTT 52 4211 4230 94 GACCCAAATT 532697 1298 1317 Exon GGTCTTCATA 59 n/a n/a 95 7-8 ATTGATTTCA Juncion 532698 1304 1323 Exon ACTTGTGGTC 52 n/a n/a 96 7-8 TTCATAATTG Juncion 532699 1310 1329 Exon ACTTCAACTT 85 n/a n/a 97 7-8 GTGGTCTTCA Juncion 532700 1316 1335 Exon8 TCCCTGACTT 96 4609 4628 98 CAACTTGTGG 532701 1322 1341 Exon8 TGTTAGTCCC 56 4615 4634 99 TGACTTCAAC 532702 1328 1347 Exon8 TCTTGGTGTT 86 4621 4640 100 AGTCCCTGAC 532703 1349 1368 Exon8 TGTACACTGC 35 4642 4661 101 CTGGAGGGCC 532704 1355 1374 Exon8 TCATGCTGTA 12 4648 4667 102 CACTGCCTGG 532705 1393 1412 Exon8 GTTCCAGCCT 27 4686 4705 103 TCAGGAGGGA 532706 1399 1418 Exon8 GGTGCGGTTC 67 4692 4711 104 CAGCCTTCAG 532707 1405 1424 Exon8 ATGGCGGGTG 26 4698 4717 105 CGGTTCCAGC 532708 1411 1430 Exon8 GATGACATGG 28 4704 4723 106 CGGGTGCGGT 532709 1417 1436 Exon8 GAGGATGATG 6 4710 4729 107 ACATGGCGGG 532710 1443 1462 Exon CCCATGTTGT 35 n/a n/a 108 8-9 GCAATCCATC Junc- tion 532711 1449 1468 Exon9 TCCCCGCCCA 28 5023 5042 109 TGTTGTGCAA 532712 1455 1474 Exon9 ATTGGGTCCC 19 5029 5048 110 CGCCCATGTT 532713 1461 1480 Exon9 ACAGTAATTG 29 5035 5054 111 GGTCCCCGCC 532714 1467 1486 Exon9 TCAATGACAG 49 5041 5060 112 TAATTGGGTC 532715 1473 1492 Exon9 ATCTCATCAA 45 5047 5066 113 TGACAGTAAT 532716 1479 1498 Exon9 TCCCGGATCT 54 5053 5072 114 CATCAATGAC 532717 1533 1552 Exon ACATCCAGAT 22 n/a n/a 115 9- AATCCTCCCT 10 Junc- tion 532718 1539 1558 Exon ACATAGACAT 8 n/a n/a 116 9- CCAGATAATC 10 Junc- tion 532719 1545 1564 Exon CCAAACACAT 30 n/a n/a 117 9- AGACATCCAG 10 Junc- tion 532720 1582 1601 Exon10 AGCATTGATG 62 5231 5250 118 TTCACTTGGT 532721 1588 1607 Exon10 AGCCAAAGCA 46 5237 5256 119 TTGATGTTCA 532722 1594 1613 Exon10 CTTGGAAGCC 35 5243 5262 120 AAAGCATTGA 532723 1600 1619 Exon10 GTCTTTCTTG 43 5249 5268 121 GAAGCCAAAG 532724 1606 1625 Exon10 CTCATTGTCT 40 5255 5274 122 TTCTTGGAAG 532725 1612 1631 Exon10 ATGTTGCTCA 49 5261 5280 123 TTGTCTTTCT 532726 1618 1637 Exon10 GAACACATGT 68 5267 5286 124 TGCTCATTGT 532727 1624 1643 Exon10 GACTTTGAAC 54 5273 5292 125 ACATGTTGCT 532728 1630 1649 Exon10 ATCCTTGACT 61 5279 5298 126 TTGAACACAT 532729 1636 1655 Exon10 TTCCATATCC 55 5285 5304 127 TTGACTTTGA 532730 1642 1661 Exon10 CAGGTTTTCC 51 5291 5310 440 ATATCCTTGA 532731 1686 1705 Exon10- CTCAGAGACT 41 5827 5846 129 11 GGCTTTCATC Junc- tion 532732 1692 1711 Exon11 CAGAGACTCA 59 5833 5852 130 GAGACTGGCT 516252 1698 1717 Exon11 ATGCCACAGA 57 5839 5858 131 GACTCAGAGA 532733 1704 1723 Exon11 CAAACCATGC 34 5845 5864 132 CACAGAGACT 532734 1710 1729 Exon11 TGTTCCCAAA 51 5851 5870 133 CCATGCCACA 532735 1734 1753 Exon11 TTGTGGTAAT 50 5875 5894 134 CGGTACCCTT 532736 1740 1759 Exon11 GGTTGCTTGT 64 5881 5900 135 GGTAATCGGT 532737 1746 1765 Exon11 TGCCATGGTT 40 5887 5906 136 GCTTGTGGTA 532738 1752 1771 Exon11 TTGGCCTGCC 49 5893 5912 137 ATGGTTGCTT 532739 1758 1777 Exon11 GAGATCTTGG 47 5899 5918 138 CCTGCCATGG 532740 1803 1822 Exon12 ACAGCCCCCA 48 6082 6101 139 TACAGCTCTC 532741 1809 1828 Exon12 GACACCACAG 40 6088 6107 140 CCCCCATACA 532742 1815 1834 Exon12 TACTCAGACA 33 6094 6113 141 CCACAGCCCC 532743 1821 1840 Exon12 ACAAAGTACT 39 6100 6119 142 CAGACACCAC 532744 1827 1846 Exon12 GTCAGCACAA 45 6106 6125 143 AGTACTCAGA 532745 1872 1891 Exon12 TTGATTGAGT 42 6151 6170 144 GTTCCTTGTC 532746 1878 1897 Exon12 CTGACCTTGA 53 6157 6176 145 TTGAGTGTTC 532747 1909 1928 Exon13 TATCTCCAGG 31 6403 6422 146 TCCCGCTTCT 532748 1967 1986 Exon13 GAATTCCTGC 30 6461 6480 147 TTCTTTTTTC 532749 1973 1992 Exon13 ATTCAGGAAT 40 6467 6486 148 TCCTGCTTCT 532750 1979 1998 Exon13 CATAAAATTC 45 6473 6492 149 AGGAATTCCT 532751 1985 2004 Exon13 CATAGTCATA 43 6479 6498 150 AAATTCAGGA 532752 2006 2025 Exon13 TGAGCTTGAT 61 6500 6519 151 CAGGGCAACG 532753 2012 2031 Exon13 TATTCTTGAG 47 6506 6525 152 CTTGATCAGG 532754 2048 2067 Exon GACAAATGGG 35 n/a n/a 153 13- CCTGATAGTC 14 Junc- tion 532755 2070 2089 Exon14 GTTGTTCCCT 43 6659 6678 154 CGGTGCAGGG 532756 2076 2095 Exon14 GCTCGAGTTG 51 6665 6684 155 TTCCCTCGGT 532757 2082 2101 Exon14 CTCAAAGCTC 36 6671 6690 156 GAGTTGTTCC 532758 2088 2107 Exon14 GGAAGCCTCA 54 6677 6696 157 AAGCTCGAGT 532759 2094 2113 Exon14 GTTGGAGGAA 52 6683 6702 158 GCCTCAAAGC 532760 2100 2119 Exon14 GTGGTAGTTG 22 6689 6708 159 GAGGAAGCCT 532761 2106 2125 Exon14 TGGCAAGTGG 34 6695 6714 160 TAGTTGGAGG 532762 2112 2131 Exon14 TGTTGCTGGC 52 6701 6720 161 AAGTGGTAGT

Example 3: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells by MOE Gapmers

[0440] Additional antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 5,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0441] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as 5-10-5 MOE gapmers. The gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. Each nucleoside in the 5 wing segment and each nucleoside in the 3 wing segment has a 2-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity. In case the sequence alignment for a target gene in a particular table is not shown, it is understood that none of the oligonucleotides presented in that table align with 100% complementarity with that target gene.

TABLE-US-00008 TABLE7 InhibitionofCFBmRNAby5-10-5 MOEgapmerstargetingSEQIDNO:1 SEQ SEQ ID ID % NO: NO: in- 1 1 hi- SEQ ISIS start stop Target bi- ID NO site site region Sequence tion NO: 588570 150 169 Exon1 TGGTCACATT 54 396 CCCTTCCCCT 588571 152 171 Exon1 CCTGGTCACA 63 397 TTCCCTTCCC 532614 154 173 Exon1 GACCTGGTCA 64 12 CATTCCCTTC 588572 156 175 Exon1 TAGACCTGGT 62 398 CACATTCCCT 588573 158 177 Exon1 CCTAGACCTG 53 399 GTCACATTCC 588566 2189 2208 Exon15 CCTTCCGAGT 60 400 CAGCTTTTTC 588567 2191 2210 Exon15 CTCCTTCCGA 61 401 GTCAGCTTTT 532770 2193 2212 Exon15 ACCTCCTTCC 77 198 GAGTCAGCTT 588568 2195 2214 Exon15 AGACCTCCTT 72 402 CCGAGTCAGC 588569 2197 2216 Exon15 GTAGACCTCC 46 403 TTCCGAGTCA 588574 2453 2472 Exon18 TTTGCCGCTT 46 404 CTGGTTTTTG 588575 2455 2474 Exon18 CTTTTGCCGC 41 405 TTCTGGTTTT 532800 2457 2476 Exon18 TGCTTTTGCC 69 228 GCTTCTGGTT 588576 2459 2478 Exon18 CCTGCTTTTG 61 406 CCGCTTCTGG 588577 2461 2480 Exon18 TACCTGCTTT 51 407 TGCCGCTTCT 516350 2550 2569 Exon18 AGAAAACCCA 71 408 AATCCTCATC 588509 2551 2570 Exon18 TAGAAAACCC 58 409 AAATCCTCAT 588510 2552 2571 Exon18 ATAGAAAACC 57 410 CAAATCCTCA 588511 2553 2572 Exon18 TATAGAAAAC 57 411 CCAAATCCTC 588512 2554 2573 Exon18 TTATAGAAAA 44 412 CCCAAATCCT 588513 2555 2574 Exon18 CTTATAGAAA 37 413 ACCCAAATCC 588514 2556 2575 Exon18 CCTTATAGAA 50 414 AACCCAAATC 588515 2557 2576 Exon18 CCCTTATAGA 45 415 AAACCCAAAT 588516 2558 2577 Exon18 CCCCTTATAG 60 416 AAAACCCAAA 588517 2559 2578 Exon18 ACCCCTTATA 67 417 GAAAACCCAA 588518 2560 2579 Exon18 AACCCCTTAT 57 418 AGAAAACCCA 588519 2561 2580 Exon18 AAACCCCTTA 61 419 TAGAAAACCC 588520 2562 2581 Exon18 GAAACCCCTT 27 420 ATAGAAAACC 588521 2563 2582 Exon18 GGAAACCCCT 25 421 TATAGAAAAC 588522 2564 2583 Exon18 AGGAAACCCC 36 422 TTATAGAAAA 588523 2565 2584 Exon18 CAGGAAACCC 36 423 CTTATAGAAA 588524 2566 2585 Exon18 GCAGGAAACC 46 424 CCTTATAGAA 588525 2567 2586 Exon18 AGCAGGAAAC 38 425 CCCTTATAGA 588526 2568 2587 Exon18 CAGCAGGAAA 47 426 CCCCTTATAG 588527 2569 2588 Exon18 CCAGCAGGAA 68 427 ACCCCTTATA 588528 2570 2589 Exon18 TCCAGCAGGA 63 428 AACCCCTTAT 532809 2571 2590 Exon18 GTCCAGCAGG 85 237 AAACCCCTTA 588529 2572 2591 Exon18 TGTCCAGCAG 76 429 GAAACCCCTT 588530 2573 2592 Exon18 CTGTCCAGCA 74 430 GGAAACCCCT 588531 2574 2593 Exon18 CCTGTCCAGC 75 431 AGGAAACCCC 588532 2575 2594 Exon18 CCCTGTCCAG 73 432 CAGGAAACCC 588533 2576 2595 Exon18 CCCCTGTCCA 82 433 GCAGGAAACC 532810 2577 2596 Exon18 GCCCCTGTCC 88 238 AGCAGGAAAC 588534 2578 2597 Exon18 CGCCCCTGTC 86 434 CAGCAGGAAA 588535 2579 2598 Exon18 ACGCCCCTGT 86 435 CCAGCAGGAA 588536 2580 2599 Exon18 CACGCCCCTG 93 436 TCCAGCAGGA 588537 2581 2600 Exon18 CCACGCCCCT 92 437 GTCCAGCAGG 588538 2582 2601 Exon18 CCCACGCCCC 94 438 TGTCCAGCAG 588539 2583 2602 Exon18 TCCCACGCCC 96 439 CTGTCCAGCA 588540 2584 2603 Exon18 ATCCCACGCC 88 440 CCTGTCCAGC 588541 2585 2604 Exon18 AATCCCACGC 79 441 CCCTGTCCAG 588542 2586 2605 Exon18 CAATCCCACG 83 442 CCCCTGTCCA 588543 2587 2606 Exon18 TCAATCCCAC 86 443 GCCCCTGTCC 588544 2588 2607 Exon18 TTCAATCCCA 90 444 CGCCCCTGTC 588545 2589 2608 Exon18 ATTCAATCCC 92 445 ACGCCCCTGT 588546 2590 2609 Exon18 AATTCAATCC 92 446 CACGCCCCTG 588547 2591 2610 Exon18 TAATTCAATC 88 447 CCACGCCCCT 588548 2592 2611 Exon18 TTAATTCAAT 93 448 CCCACGCCCC 588549 2593 2612 Exon18 TTTAATTCAA 88 449 TCCCACGCCC 588550 2594 2613 Exon18 TTTTAATTCA 89 450 ATCCCACGCC 588551 2595 2614 Exon18 GTTTTAATTC 94 451 AATCCCACGC 588552 2596 2615 Exon18 TGTTTTAATT 93 452 CAATCCCACG 588553 2597 2616 Exon18 CTGTTTTAAT 96 453 TCAATCCCAC 588554 2598 2617 Exon18 GCTGTTTTAA 98 454 TTCAATCCCA 532811 2599 2618 Exon18 AGCTGTTTTA 97 239 ATTCAATCCC 532811 2599 2618 Exon18 AGCTGTTTTA 95 239 ATTCAATCCC 588555 2600 2619 Exon18 CAGCTGTTTT 93 455 AATTCAATCC 588556 2601 2620 Exon18 GCAGCTGTTT 96 456 TAATTCAATC 588557 2602 2621 Exon18 CGCAGCTGTT 98 457 TTAATTCAAT 588558 2603 2622 Exon18 TCGCAGCTGT 95 458 TTTAATTCAA 532917 2604 2623 Exon18 GTCGCAGCTG 97 317 TTTTAATTCA 588559 2605 2624 Exon18 TGTCGCAGCT 95 459 GTTTTAATTC 588560 2606 2625 Exon18 TTGTCGCAGC 92 460 TGTTTTAATT 588561 2607 2626 Exon18 GTTGTCGCAG 93 461 CTGTTTTAAT 532952 2608 2627 Exon18 TGTTGTCGCA 88 395 GCTGTTTTAA 588562 2609 2628 Exon18/ TTGTTGTCGC 90 462 Repeat AGCTGTTTTA 588563 2610 2629 Exon18/ TTTGTTGTCG 89 463 Repeat CAGCTGTTTT 588564 2611 2630 Exon18/ TTTTGTTGTC 92 464 Repeat GCAGCTGTTT 588565 2612 2631 Exon18/ TTTTTGTTGT 88 465 Repeat CGCAGCTGTT

TABLE-US-00009 TABLE8 InhibitionofCFBmRNAby5-10-5MOEgapmers targetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: % NO: NO: 1 1 inhi 2 2 SEQ ISIS start stop Target bi- start stop ID NO site site region Sequence tion site site NO: 588685 n/a n/a Exon1 GGATCCAGCT 48 1596 1615 466 CACTCCCCTG 588686 n/a n/a Exon1 AAATAAGGAT 29 1602 n/a 467 CCAGCTCACT 588688 n/a n/a Exon1 GACCAGAAAT 58 1608 1627 468 AAGGATCCAG 588690 n/a n/a Exon1 CTTAGGGACC 45 1614 1633 469 AGAAATAAGG 588692 n/a n/a Exon1 CACCCACTTA 36 1620 1639 470 GGGACCAGAA 588694 n/a n/a Exon1 ACCACCCACT 47 1622 1641 471 TAGGGACCAG 588696 n/a n/a Exon1 AGGTCCAGGA 96 1685 1704 472 CTCTCCCCTT 588698 n/a n/a Exon1 AAGGTCCAGG 96 1686 1705 473 ACTCTCCCCT 588700 n/a n/a Exon1 AAACTGCAGA 2 1716 1735 474 AGTCCCACCC 588586 30 49 Exon1 GGAGGGCCCC 59 1751 1770 475 GCTGAGCTGC 588587 48 67 Exon1 TCCCGGAACA 45 1769 1788 476 TCCAAGCGGG 588588 56 75 Exon1 CATCACTTTC 39 1777 n/a 477 CCGGAACATC 588589 151 170 Exon1 CTGGTCACAT 29 1872 1891 478 TCCCTTCCCC 588590 157 176 Exon1 CTAGACCTGG 47 1878 1897 479 TCACATTCCC 588591 339 358 Exon GGAGTGGTGG 44 n/a n/a 480 1-2 TCACACCTCC Junc- tion 588592 384 403 Exon2 ACCCCCTCCA 43 2192 2211 481 GAGAGCAGGA 588593 390 409 Exon2 ATCTCTACCC 34 2198 2217 482 CCTCCAGAGA 588594 467 486 Exon2 GGTACGGGTA 17 2275 2294 483 GAAGCCAGAA 588595 671 690 Exon3 GGAGAGTGTA 37 2879 2898 484 ACCGTCATAG 588596 689 708 Exon3 TGCGATTGGC 18 2897 2916 485 AGAGCCCCGG 588597 695 714 Exon3 GGCAGGTGCG 32 2903 2922 486 ATTGGCAGAG 588598 707 726 Exon3 GGCCATTCAC 45 2915 2934 487 TTGGCAGGTG 588599 738 757 Exon3 TTGTCACAGA 52 2946 2965 488 TCGCTGTCTG 588600 924 943 Exon AAGGAGTCTT 39 n/a n/a 489 4-5 GGCAGGAAGG Junc- tion 588601 931 950 Exon GTACATGAAG 37 n/a n/a 490 4-5 GAGTCTTGGC Junc- tion 588602 959 978 Exon5 AAGCTTCGGC 21 3542 3561 491 CACCTCTTGA 588603 1089 1108 Exon6 CCATCTAGCA 22 3773 3792 492 CCAGGTAGAT 588604 1108 1127 Exon6 GGCCCCAATG 21 3792 3811 493 CTGTCTGATC 588606 1150 1169 Exon6 AATTAAGTTG 56 3834 3853 494 ACTAGACACT 588608 1162 1181 Exon TGCCACCTTC 50 19 495 6-7 TCAATTAAGT Junc- tion 588578 1167 1186 Exon TAACTTGCCA 23 n/a n/a 496 6-7 CCTTCTCAAT Junc- tion 588579 1169 1188 Exon CATAACTTGC 23 n/a n/a 497 6-7 CACCTTCTCA Junc- tion 532692 1171 1190 Exon ACCATAACTT 15 n/a n/a 90 6-7 GCCACCTTCT Junc- tion 588580 1173 1192 Exon ACACCATAAC 16 n/a n/a 498 6-7 TTGCCACCTT Junc- tion 588581 1175 1194 Exon TCACACCATA 14 4151 4170 499 6-7 ACTTGCCACC Junc- tion 588610 1319 1338 Exon8 TAGTCCCTGA 50 4612 4631 500 CTTCAACTTG 588612 1325 1344 Exon8 TGGTGTTAGT 47 4618 4637 501 CCCTGACTTC 588614 1396 1415 Exon8 GCGGTTCCAG 47 4689 4708 502 CCTTCAGGAG 588616 1421 1440 Exon8 TCATGAGGAT 51 4714 4733 503 GATGACATGG 588618 1446 1465 Exon9 CCGCCCATGT 18 5020 5039 504 TGTGCAATCC 588620 1458 1477 Exon9 GTAATTGGGT 40 5032 5051 505 CCCCGCCCAT 588623 1482 1501 Exon9 AAGTCCCGGA 40 5056 5075 506 TCTCATCAAT 588624 1542 1561 Exon AACACATAGA 45 n/a n/a 507 9- CATCCAGATA 10 Junc- tion 588626 1585 1604 Exon10 CAAAGCATTG 43 5234 5253 508 ATGTTCACTT 588628 1621 1640 Exon10 TTTGAACACA 45 5270 5289 509 TGTTGCTCAT 588631 1646 1665 Exon10 CTTCCAGGTT 53 5295 5314 510 TTCCATATCC 588632 1647 1666 Exon10 TCTTCCAGGT 56 5296 5315 511 TTTCCATATC 588634 1689 1708 Exon11 AGACTCAGAG 35 5830 5849 512 ACTGGCTTTC 588636 1749 1768 Exon11 GCCTGCCATG 55 5890 5909 513 GTTGCTTGTG 588638 1763 1782 Exon11 TGACTGAGAT 78 5904 5923 514 CTTGGCCTGC 588640 1912 1931 Exon13 TTCTATCTCC 95 6406 6425 515 AGGTCCCGCT 588642 1982 2001 Exon13 AGTCATAAAA 44 6476 6495 516 TTCAGGAATT 588645 2073 2092 Exon14 CGAGTTGTTC 40 6662 6681 517 CCTCGGTGCA 588646 2085 2104 Exon14 AGCCTCAAAG 57 6674 6693 518 CTCGAGTTGT 588648 2091 2110 Exon14 GGAGGAAGCC 48 6680 6699 519 TCAAAGCTCG 588651 2097 2116 Exon14 GTAGTTGGAG 40 6686 6705 520 GAAGCCTCAA 588652 2103 2122 Exon14 CAAGTGGTAG 43 6692 6711 521 TTGGAGGAAG 588654 2166 2185 Exon15 TCCTCAGACA 13 6954 6973 522 CAAACAGAGC 588656 2172 2191 Exon15 TTCTCCTCCT 55 6960 6979 523 CAGACACAAA 588658 2196 2215 Exon15 TAGACCTCCT 44 6984 7003 524 TCCGAGTCAG 588660 2202 2221 Exon15 TTGATGTAGA 50 6990 7009 525 CCTCCTTCCG 588582 2219 2238 Exon CTTTCTTATC 19 n/a n/a 526 15- CCCATTCTTG 16 Junc- tion 588583 2221 2240 Exon GCCTTTCTTA 14 n/a n/a 527 15- TCCCCATTCT 16 Junc- tion 532775 2223 2242 Exon CTGCCTTTCT 3 n/a n/a 203 15- TATCCCCATT 16 Junc- tion 588584 2225 2244 Exon AGCTGCCTTT 18 n/a n/a 528 15- CTTATCCCCA 16 Junc- tion 588662 2226 2245 Exon CAGCTGCCTT 27 n/a n/a 529 15- TCTTATCCCC 16 Junc- tion 588585 2227 2246 Exon ACAGCTGCCT 59 n/a n/a 530 15- TTCTTATCCC 16 Junc- tion 588664 2238 2257 Exon16 GCATCTCTCT 49 7122 7141 531 CACAGCTGCC 588666 2276 2295 Exon16 AGATGTCCTT 41 7160 7179 532 GACTTTGTCA 588668 2330 2349 Exon16 CAGCATAGGG 41 7214 7233 533 ACTCACTCCT 588670 2361 2380 Exon CCGCCAGAAT 43 n/a n/a 534 16- CACCTCTGCA 17 Junc- tion 588672 2397 2416 Exon17 TGAATGAAAC 52 7362 7381 535 GACTTCTCTT 588674 2430 2449 Exon18 ACATCCACTA 39 7665 7684 536 CTCCCCAGCT 588676 2448 2467 Exon18 CGCTTCTGGT 69 7683 7702 537 TTTTGCAGAC 588678 2454 2473 Exon18 TTTTGCCGCT 46 7689 7708 538 TCTGGTTTTT 588680 2466 2485 Exon18 GCAGGTACCT 47 7701 7720 539 GCTTTTGCCG 588682 2532 2551 Exon18 TCTTGGAGTT 58 7767 7786 540 TCTCCTTCAG 532811 2599 2618 Exon18 AGCTGTTTTA 10 7834 7853 239 ATTCAATCCC 532917 2604 2623 Exon18 GTCGCAGCTG 11 7839 7858 317 TTTTAATTCA

Example 4: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells by MOE Gapmers

[0442] Antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 3,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0443] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as 4-8-5 MOE, 5-9-5 MOE, 5-10-5 MOE, 3-10-4 MOE, 3-10-7 MOE, 6-7-6-MOE, 6-8-6 MOE, or 5-7-5 MOE gapmers, or as deoxy, MOE, and cEt oligonucleotides.

[0444] The 4-8-5 MOE gapmers are 17 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising four and five nucleosides respectively. The 5-9-5 MOE gapmers are 19 nucleosides in length, wherein the central gap segment comprises of nine 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 5-10-5 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 5-7-5 MOE gapmers are 17 nucleosides in length, wherein the central gap segment comprises of seven 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 3-10-4 MOE gapmers are 17 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising three and four nucleosides respectively. The 3-10-7 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising three and seven nucleosides respectively. The 6-7-6 MOE gapmers are 19 nucleosides in length, wherein the central gap segment comprises of seven 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising six nucleosides each. The 6-8-6 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising six nucleosides each. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

[0445] The deoxy, MOE and cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an cEt sugar modification, or a deoxy modification. The Chemistry column describes the sugar modifications of each oligonucleotide. k indicates an cEt sugar modification; d indicates deoxyribose; and e indicates a MOE modification.

[0446] Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity.

TABLE-US-00010 TABLE9 InhibitionofCFBmRNAbydeoxy,MOEandcEtoligonucleotidestargetingSEQIDNO:1or SEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS Start stop Target %in- Start Stop ID NO site site region Sequence hibition site site Motif NO: 532811 2599 2618 Exon18 AGCTGTTTTAATTCAATCCC 10 7834 7853 eeeeeddddddddddee 239 eee 588884 48 63 Exon1 GGAACATCCAAGCGGG 79 1769 1784 eekddddddddddkke 541 588872 154 169 Exon1 TGGTCACATTCCCTTC 91 1875 1890 eekddddddddddkke 542 588873 156 171 Exon1 CCTGGTCACATTCCCT 91 1877 1892 eekddddddddddkke 543 588874 158 173 Exon1 GACCTGGTCACATTCC 91 1879 1894 eekddddddddddkke 544 588878 1171 1186 Exon6-7 TAACTTGCCACCTTCT 92 n/a n/a eekddddddddddkke 545 Junction 588879 1173 1188 Exon6-7 CATAACTTGCCACCTT 94 n/a n/a eekddddddddddkke 546 Junction 588880 1175 1190 Exon6-7 ACCATAACTTGCCACC 89 4151 4166 eekddddddddddkke 547 Junction 588869 2193 2208 Exon15 CCTTCCGAGTCAGCTT 17 6981 6996 eekddddddddddkke 548 588870 2195 2210 Exon15 CTCCTTCCGAGTCAGC 78 6983 6998 eekddddddddddkke 549 588871 2197 2212 Exon15 ACCTCCTTCCGAGTCA 80 6985 7000 eekddddddddddkke 550 588881 2223 2238 Exon15- CTTTCTTATCCCCATT 93 n/a n/a eekddddddddddkke 551 16 Junction 588882 2225 2240 Exon15- GCCTTTCTTATCCCCA 88 n/a n/a eekddddddddddkke 552 16 Junction 588883 2227 2242 Exon15- CTGCCTTTCTTATCCC 90 n/a n/a eekddddddddddkke 553 16 Junction 588875 2457 2472 Exon18 TTTGCCGCTTCTGGTT 81 7692 7707 eekddddddddddkke 554 588876 2459 2474 Exon18 CTTTTGCCGCTTCTGG 95 7694 7709 eekddddddddddkke 555 588877 2461 2476 Exon18 TGCTTTTGCCGCTTCT 91 7696 7711 eekddddddddddkke 556 588807 2551 2566 Exon18 AAACCCAAATCCTCAT 82 7786 7801 eekddddddddddkke 557 588808 2553 2568 Exon18 GAAAACCCAAATCCTC 69 7788 7803 eekddddddddddkke 558 588809 2555 2570 Exon18 TAGAAAACCCAAATCC 51 7790 7805 eekddddddddddkke 559 588810 2556 2571 Exon18 ATAGAAAACCCAAATC 23 7791 7806 eekddddddddddkke 560 588811 2559 2574 Exon18 CTTATAGAAAACCCAA 13 7794 7809 eekddddddddddkke 561 588812 2560 2575 Exon18 CCTTATAGAAAACCCA 29 7795 7810 eekddddddddddkke 562 588813 2561 2576 Exon18 CCCTTATAGAAAACCC 53 7796 7811 eekddddddddddkke 563 588814 2562 2577 Exon18 CCCCTTATAGAAAACC 86 7797 7812 eekddddddddddkke 564 588815 2563 2578 Exon18 ACCCCTTATAGAAAAC 76 7798 7813 eekddddddddddkke 565 588816 2564 2579 Exon18 AACCCCTTATAGAAAA 33 7799 7814 eekddddddddddkke 566 588817 2565 2580 Exon18 AAACCCCTTATAGAAA 48 7800 7815 eekddddddddddkke 567 588818 2566 2581 Exon18 GAAACCCCTTATAGAA 44 7801 7816 eekddddddddddkke 568 588819 2567 2582 Exon18 GGAAACCCCTTATAGA 74 7802 7817 eekddddddddddkke 569 588820 2568 2583 Exon18 AGGAAACCCCTTATAG 68 7803 7818 eekddddddddddkke 570 588821 2569 2584 Exon18 CAGGAAACCCCTTATA 45 7804 7819 eekddddddddddkke 571 588822 2570 2585 Exon18 GCAGGAAACCCCTTAT 50 7805 7820 eekddddddddddkke 572 588823 2571 2586 Exon18 AGCAGGAAACCCCTTA 54 7806 7821 eekddddddddddkke 573 588824 2572 2587 Exon18 CAGCAGGAAACCCCTT 35 7807 7822 eekddddddddddkke 574 588825 2573 2588 Exon18 CCAGCAGGAAACCCCT 11 7808 7823 eekddddddddddkke 575 588826 2574 2589 Exon18 TCCAGCAGGAAACCCC 19 7809 7824 eekddddddddddkke 576 588827 2575 2590 Exon18 GTCCAGCAGGAAACCC 42 7810 7825 eekddddddddddkke 577 588828 2576 2591 Exon18 TGTCCAGCAGGAAACC 0 7811 7826 eekddddddddddkke 578 588829 2577 2592 Exon18 CTGTCCAGCAGGAAAC 49 7812 7827 eekddddddddddkke 579 588830 2578 2593 Exon18 CCTGTCCAGCAGGAAA 11 7813 7828 eekddddddddddkke 580 588831 2579 2594 Exon18 CCCTGTCCAGCAGGAA 20 7814 7829 eekddddddddddkke 581 588832 2580 2595 Exon18 CCCCTGTCCAGCAGGA 19 7815 7830 eekddddddddddkke 582 588833 2581 2596 Exon18 GCCCCTGTCCAGCAGG 12 7816 7831 eekddddddddddkke 583 588834 2582 2597 Exon18 CGCCCCTGTCCAGCAG 10 7817 7832 eekddddddddddkke 584 588835 2583 2598 Exon18 ACGCCCCTGTCCAGCA 13 7818 7833 eekddddddddddkke 585 588836 2584 2599 Exon18 CACGCCCCTGTCCAGC 13 7819 7834 eekddddddddddkke 586 588837 2585 2600 Exon18 CCACGCCCCTGTCCAG 39 7820 7835 eekddddddddddkke 587 588838 2586 2601 Exon18 CCCACGCCCCTGTCCA 54 7821 7836 eekddddddddddkke 588 588839 2587 2602 Exon18 TCCCACGCCCCTGTCC 51 7822 7837 eekddddddddddkke 589 588840 2588 2603 Exon18 ATCCCACGCCCCTGTC 65 7823 7838 eekddddddddddkke 590 588841 2589 2604 Exon18 AATCCCACGCCCCTGT 59 7824 7839 eekddddddddddkke 591 588842 2590 2605 Exon18 CAATCCCACGCCCCTG 70 7825 7840 eekddddddddddkke 592 588843 2591 2606 Exon18 TCAATCCCACGCCCCT 0 7826 7841 eekddddddddddkke 593 588844 2592 2607 Exon18 TTCAATCCCACGCCCC 48 7827 7842 eekddddddddddkke 594 588845 2593 2608 Exon18 ATTCAATCCCACGCCC 46 7828 7843 eekddddddddddkke 595 588846 2594 2609 Exon18 AATTCAATCCCACGCC 67 7829 7844 eekddddddddddkke 596 588847 2595 2610 Exon18 TAATTCAATCCCACGC 75 7830 7845 eekddddddddddkke 597 588848 2596 2611 Exon18 TTAATTCAATCCCACG 76 7831 7846 eekddddddddddkke 598 588849 2597 2612 Exon18 TTTAATTCAATCCCAC 94 7832 7847 eekddddddddddkke 599 588850 2598 2613 Exon18 TTTTAATTCAATCCCA 91 7833 7848 eekddddddddddkke 600 588851 2599 2614 Exon18 GTTTTAATTCAATCCC 91 7834 7849 eekddddddddddkke 601 588852 2600 2615 Exon18 TGTTTTAATTCAATCC 78 7835 7850 eekddddddddddkke 602 588853 2601 2616 Exon18 CTGTTTTAATTCAATC 81 7836 7851 eekddddddddddkke 603 588854 2602 2617 Exon18 GCTGTTTTAATTCAAT 63 7837 7852 eekddddddddddkke 604 588855 2603 2618 Exon18 AGCTGTTTTAATTCAA 65 7838 7853 eekddddddddddkke 605 588856 2604 2619 Exon18 CAGCTGTTTTAATTCA 76 7839 7854 eekddddddddddkke 606 588857 2605 2620 Exon18 GCAGCTGTTTTAATTC 89 7840 7855 eekddddddddddkke 607 588858 2606 2621 Exon18 CGCAGCTGTTTTAATT 89 7841 7856 eekddddddddddkke 608 588859 2607 2622 Exon18 TCGCAGCTGTTTTAAT 89 7842 7857 eekddddddddddkke 609 588860 2608 2623 Exon18 GTCGCAGCTGTTTTAA 76 7843 7858 eekddddddddddkke 610 588861 2609 2624 Exon18 TGTCGCAGCTGTTTTA 87 7844 7859 eekddddddddddkke 611 588862 2610 2625 Exon18 TTGTCGCAGCTGTTTT 85 7845 7860 eekddddddddddkke 612 588863 2611 2626 Exon18 GTTGTCGCAGCTGTTT 87 7846 7861 eekddddddddddkke 613 588864 2612 2627 Exon18 TGTTGTCGCAGCTGTT 67 7847 7862 eekddddddddddkke 614 588865 2613 2628 Exon18 TTGTTGTCGCAGCTGT 51 n/a n/a eekddddddddddkke 615 588866 2614 2629 Exon18 TTTGTTGTCGCAGCTG 95 n/a n/a eekddddddddddkke 616 588867 2615 2630 Exon18 TTTTGTTGTCGCAGCT 92 n/a n/a eekddddddddddkke 617 588868 2616 2631 Exon18 TTTTTGTTGTCGCAGC 66 n/a n/a eekddddddddddkke 618

TABLE-US-00011 TABLE10 InhibitionofCFBmRNAby5-10-5MOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID IDNO: IDNO: NO:1 NO:1 2 2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site NO: 588685 n/a n/a Exon1 GGATCCAGCTCACTCCCCTG 14 1596 1615 466 588686 n/a n/a Exon1 AAATAAGGATCCAGCTCACT 2 1602 1621 467 588688 n/a n/a Exon1 GACCAGAAATAAGGATCCAG 3 1608 1627 468 588690 n/a n/a Exon1 CTTAGGGACCAGAAATAAGG 10 1614 1633 469 588692 n/a n/a Exon1 CACCCACTTAGGGACCAGAA 23 1620 1639 470 588694 n/a n/a Exon1 ACCACCCACTTAGGGACCAG 23 1622 1641 471 588696 n/a n/a Exon1 AGGTCCAGGACTCTCCCCTT 15 1685 1704 472 588698 n/a n/a Exon1 AAGGTCCAGGACTCTCCCCT 19 1686 1705 473 588700 n/a n/a Exon1 AAACTGCAGAAGTCCCACCC 16 1716 1735 474 588586 30 49 Exon1 GGAGGGCCCCGCTGAGCTGC 11 1751 1770 475 588587 48 67 Exon1 TCCCGGAACATCCAAGCGGG 14 1769 1788 476 588588 56 75 Exon1 CATCACTTTCCCGGAACATC 18 1777 1796 477 588589 151 170 Exon1 CTGGTCACATTCCCTTCCCC 59 1872 1891 478 588590 157 176 Exon1 CTAGACCTGGTCACATTCCC 59 1878 1897 479 588591 339 358 Exon1-2 GGAGTGGTGGTCACACCTCC 45 n/a n/a 480 Junction 588592 384 403 Exon2 ACCCCCTCCAGAGAGCAGGA 39 2192 2211 481 588593 390 409 Exon2 ATCTCTACCCCCTCCAGAGA 29 2198 2217 482 588594 467 486 Exon2 GGTACGGGTAGAAGCCAGAA 47 2275 2294 483 588595 671 690 Exon3 GGAGAGTGTAACCGTCATAG 44 2879 2898 484 588596 689 708 Exon3 TGCGATTGGCAGAGCCCCGG 43 2897 2916 638 588597 695 714 Exon3 GGCAGGTGCGATTGGCAGAG 34 2903 2922 486 588598 707 726 Exon3 GGCCATTCACTTGGCAGGTG 17 2915 2934 487 588599 738 757 Exon3 TTGTCACAGATCGCTGTCTG 37 2946 2965 488 588600 924 943 Exon3-4 AAGGAGTCTTGGCAGGAAGG 18 n/a n/a 489 Junction 588601 931 950 Exon3-4 GTACATGAAGGAGTCTTGGC 32 n/a n/a 490 Junction 588602 959 978 Exon5 AAGCTTCGGCCACCTCTTGA 45 3542 3561 491 588603 1089 1108 Exon6 CCATCTAGCACCAGGTAGAT 52 3773 3792 492 588604 1108 1127 Exon6 GGCCCCAATGCTGTCTGATC 39 3792 3811 493 588606 1150 1169 Exon6 AATTAAGTTGACTAGACACT 37 3834 3853 494 588608 1162 1181 Exon6-7 TGCCACCTTCTCAATTAAGT 21 n/a n/a 648 Junction 588578 1167 1186 Exon6-7 TAACTTGCCACCTTCTCAAT 22 n/a n/a 496 Junction 588579 1169 1188 Exon6-7 CATAACTTGCCACCTTCTCA 21 n/a n/a 497 Junction 532692 1171 1190 Exon6-7 ACCATAACTTGCCACCTTCT 56 n/a n/a 90 Junction 588580 1173 1192 Exon6-7 ACACCATAACTTGCCACCTT 50 n/a n/a 498 Junction 588581 1175 1194 Exon7 TCACACCATAACTTGCCACC 50 4151 4170 499 588610 1319 1338 Exon8 TAGTCCCTGACTTCAACTTG 47 4612 4631 500 588612 1325 1344 Exon8 TGGTGTTAGTCCCTGACTTC 47 4618 4637 501 588614 1396 1415 Exon8 GCGGTTCCAGCCTTCAGGAG 51 4689 4708 502 588616 1421 1440 Exon8 TCATGAGGATGATGACATGG 18 4714 4733 503 588618 1446 1465 Exon9 CCGCCCATGTTGTGCAATCC 40 5020 5039 504 588620 1458 1477 Exon9 GTAATTGGGTCCCCGCCCAT 40 5032 5051 505 588623 1482 1501 Exon9 AAGTCCCGGATCTCATCAAT 45 5056 5075 506 588624 1542 1561 Exon9-10 AACACATAGACATCCAGATA 43 n/a n/a 507 Junction 588626 1585 1604 Exon10 CAAAGCATTGATGTTCACTT 45 5234 5253 508 588628 1621 1640 Exon10 TTTGAACACATGTTGCTCAT 53 5270 5289 509 588631 1646 1665 Exon10 CTTCCAGGTTTTCCATATCC 56 5295 5314 510 588632 1647 1666 Exon10 TCTTCCAGGTTTTCCATATC 35 5296 5315 511 588634 1689 1708 Exon11 AGACTCAGAGACTGGCTTTC 55 5830 5849 512 588636 1749 1768 Exon11 GCCTGCCATGGTTGCTTGTG 78 5890 5909 513 588638 1763 1782 Exon11 TGACTGAGATCTTGGCCTGC 95 5904 5923 514 588640 1912 1931 Exon13 TTCTATCTCCAGGTCCCGCT 44 6406 6425 515 588642 1982 2001 Exon13 AGTCATAAAATTCAGGAATT 40 6476 6495 516 588645 2073 2092 Exon14 CGAGTTGTTCCCTCGGTGCA 57 6662 6681 517 588646 2085 2104 Exon14 AGCCTCAAAGCTCGAGTIGT 48 6674 6693 518 588648 2091 2110 Exon14 GGAGGAAGCCTCAAAGCTCG 40 6680 6699 519 588651 2097 2116 Exon14 GTAGTTGGAGGAAGCCTCAA 43 6686 6705 520 588652 2103 2122 Exon14 CAAGTGGTAGTTGGAGGAAG 13 6692 6711 521 588654 2166 2185 Exon15 TCCTCAGACACAAACAGAGC 55 6954 6973 522 588656 2172 2191 Exon15 TTCTCCTCCTCAGACACAAA 44 6960 6979 523 588658 2196 2215 Exon15 TAGACCTCCTTCCGAGTCAG 50 6984 7003 524 588660 2202 2221 Exon15 TTGATGTAGACCTCCTTCCG 27 6990 7009 525 588582 2219 2238 Exon15- CTTTCTTATCCCCATTCTTG 49 n/a n/a 526 16 Junction 588583 2221 2240 Exon15- GCCTTTCTTATCCCCATTCT 41 n/a n/a 527 16 Junction 532775 2223 2242 Exon15- CTGCCTTTCTTATCCCCATT 41 n/a n/a 203 16 Junction 588584 2225 2244 Exon15- AGCTGCCTTTCTTATCCCCA 43 n/a n/a 528 16 Junction 588662 2226 2245 Exon15- CAGCTGCCTTTCTTATCCCC 52 n/a n/a 529 16 Junction 588585 2227 2246 Exon15- ACAGCTGCCTTTCTTATCCC 39 n/a n/a 530 16 Junction 588664 2238 2257 Exon16 GCATCTCTCTCACAGCTGCC 69 7122 7141 531 588666 2276 2295 Exon16 AGATGTCCTTGACTTTGTCA 46 7160 7179 532 588668 2330 2349 Exon16 CAGCATAGGGACTCACTCCT 47 7214 7233 533 588670 2361 2380 Exon16- CCGCCAGAATCACCTCTGCA 58 n/a n/a 534 17 Junction 588672 2397 2416 Exon17 TGAATGAAACGACTTCTCTT 48 7362 7381 535 588674 2430 2449 Exon18 ACATCCACTACTCCCCAGCT 29 7665 7684 536 588676 2448 2467 Exon18 CGCTTCTGGTTTTTGCAGAC 58 7683 7702 537 588678 2454 2473 Exon18 TTTTGCCGCTTCTGGTTTTT 45 7689 7708 538 588680 2466 2485 Exon18 GCAGGTACCTGCTTTTGCCG 36 7701 7720 539 588682 2532 2551 Exon18 TCTTGGAGTTTCTCCTTCAG 47 7767 7786 540 532811 2599 2618 Exon18 AGCTGTTTTAATTCAATCCC 96 7834 7853 239 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 96 7839 7858 317

TABLE-US-00012 TABLE11 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO 598973 2552 2568 Exon18 GAAAACCCAAATCCTCA 40 7787 7803 3-10-4 619 599036 2552 2568 Exon18 GAAAACCCAAATCCTCA 18 7787 7803 5-7-5 619 598974 2553 2569 Exon18 AGAAAACCCAAATCCTC 28 7788 7804 3-10-4 620 599037 2553 2569 Exon18 AGAAAACCCAAATCCTC 19 7788 7804 5-7-5 620 598975 2554 2570 Exon18 TAGAAAACCCAAATCCT 15 7789 7805 3-10-4 621 599038 2554 2570 Exon18 TAGAAAACCCAAATCCT 32 7789 7805 5-7-5 621 598976 2555 2571 Exon18 ATAGAAAACCCAAATCC 12 7790 7806 3-10-4 622 599039 2555 2571 Exon18 ATAGAAAACCCAAATCC 7 7790 7806 5-7-5 622 598977 2557 2573 Exon18 TTATAGAAAACCCAAAT 13 7792 7808 3-10-4 623 599040 2557 2573 Exon18 TTATAGAAAACCCAAAT 13 7792 7808 5-7-5 623 598978 2558 2574 Exon18 CTTATAGAAAACCCAAA 0 7793 7809 3-10-4 624 599041 2558 2574 Exon18 CTTATAGAAAACCCAAA 0 7793 7809 5-7-5 624 598979 2559 2575 Exon18 CCTTATAGAAAACCCAA 8 7794 7810 3-10-4 625 599042 2559 2575 Exon18 CCTTATAGAAAACCCAA 19 7794 7810 5-7-5 625 598980 2560 2576 Exon18 CCCTTATAGAAAACCCA 42 7795 7811 3-10-4 626 599043 2560 2576 Exon18 CCCTTATAGAAAACCCA 10 7795 7811 5-7-5 626 598981 2561 2577 Exon18 CCCCTTATAGAAAACCC 20 7796 7812 3-10-4 627 599044 2561 2577 Exon18 CCCCTTATAGAAAACCC 12 7796 7812 5-7-5 627 598982 2562 2578 Exon18 ACCCCTTATAGAAAACC 10 7797 7813 3-10-4 628 599045 2562 2578 Exon18 ACCCCTTATAGAAAACC 3 7797 7813 5-7-5 628 598983 2563 2579 Exon18 AACCCCTTATAGAAAAC 0 7798 7814 3-10-4 629 599046 2563 2579 Exon18 AACCCCTTATAGAAAAC 18 7798 7814 5-7-5 629 598984 2564 2580 Exon18 AAACCCCTTATAGAAAA 0 7799 7815 3-10-4 630 599047 2564 2580 Exon18 AAACCCCTTATAGAAAA 7 7799 7815 5-7-5 630 598985 2565 2581 Exon18 GAAACCCCTTATAGAAA 0 7800 7816 3-10-4 631 599048 2565 2581 Exon18 GAAACCCCTTATAGAAA 9 7800 7816 5-7-5 631 598986 2566 2582 Exon18 GGAAACCCCTTATAGAA 0 7801 7817 3-10-4 632 599049 2566 2582 Exon18 GGAAACCCCTTATAGAA 18 7801 7817 5-7-5 632 598988 2567 2583 Exon18 AGGAAACCCCTTATAGA 0 7802 7818 3-10-4 633 599050 2567 2583 Exon18 AGGAAACCCCTTATAGA 8 7802 7818 5-7-5 633 598989 2568 2584 Exon18 CAGGAAACCCCTTATAG 0 7803 7819 3-10-4 634 598990 2569 2585 Exon18 GCAGGAAACCCCTTATA 8 7804 7820 3-10-4 635 598991 2570 2586 Exon18 AGCAGGAAACCCCTTAT 25 7805 7821 3-10-4 636 598992 2571 2587 Exon18 CAGCAGGAAACCCCTTA 12 7806 7822 3-10-4 637 598993 2572 2588 Exon18 CCAGCAGGAAACCCCTT 37 7807 7823 3-10-4 638 598994 2573 2589 Exon18 TCCAGCAGGAAACCCCT 29 7808 7824 3-10-4 639 598995 2574 2590 Exon18 GTCCAGCAGGAAACCCC 42 7809 7825 3-10-4 640 598996 2575 2591 Exon18 TGTCCAGCAGGAAACCC 36 7810 7826 3-10-4 641 598997 2576 2592 Exon18 CTGTCCAGCAGGAAACC 18 7811 7827 3-10-4 642 598998 2577 2593 Exon18 CCTGTCCAGCAGGAAAC 27 7812 7828 3-10-4 643 598999 2578 2594 Exon18 CCCTGTCCAGCAGGAAA 61 7813 7829 3-10-4 644 599000 2580 2596 Exon18 GCCCCTGTCCAGCAGGA 71 7815 7831 3-10-4 645 599001 2581 2597 Exon18 CGCCCCTGTCCAGCAGG 80 7816 7832 3-10-4 646 599002 2582 2598 Exon18 ACGCCCCTGTCCAGCAG 68 7817 7833 3-10-4 647 599003 2583 2599 Exon18 CACGCCCCTGTCCAGCA 71 7818 7834 3-10-4 648 599004 2584 2600 Exon18 CCACGCCCCTGTCCAGC 76 7819 7835 3-10-4 649 599005 2585 2601 Exon18 CCCACGCCCCTGTCCAG 70 7820 7836 3-10-4 650 599006 2586 2602 Exon18 TCCCACGCCCCTGTCCA 65 7821 7837 3-10-4 651 599007 2587 2603 Exon18 ATCCCACGCCCCTGTCC 60 7822 7838 3-10-4 652 599008 2588 2604 Exon18 AATCCCACGCCCCTGTC 72 7823 7839 3-10-4 653 599009 2589 2605 Exon18 CAATCCCACGCCCCTGT 79 7824 7840 3-10-4 654 599010 2590 2606 Exon18 TCAATCCCACGCCCCTG 73 7825 7841 3-10-4 655 599011 2591 2607 Exon18 TTCAATCCCACGCCCCT 79 7826 7842 3-10-4 656 599012 2592 2608 Exon18 ATTCAATCCCACGCCCC 67 7827 7843 3-10-4 657 599013 2593 2609 Exon18 AATTCAATCCCACGCCC 65 7828 7844 3-10-4 658 599014 2594 2610 Exon18 TAATTCAATCCCACGCC 74 7829 7845 3-10-4 659 599015 2595 2611 Exon18 TTAATTCAATCCCACGC 71 7830 7846 3-10-4 660 599016 2596 2612 Exon18 TTTAATTCAATCCCACG 48 7831 7847 3-10-4 661 599017 2597 2613 Exon18 TTTTAATTCAATCCCAC 34 7832 7848 3-10-4 662 599018 2598 2614 Exon18 GTTTTAATTCAATCCCA 56 7833 7849 3-10-4 663 599019 2599 2615 Exon18 TGTTTTAATTCAATCCC 60 7834 7850 3-10-4 664 599020 2600 2616 Exon18 CTGTTTTAATTCAATCC 0 7835 7851 3-10-4 665 599021 2601 2617 Exon18 GCTGTTTTAATTCAATC 33 7836 7852 3-10-4 666 599022 2602 2618 Exon18 AGCTGTTTTAATTCAAT 17 7837 7853 3-10-4 667 599023 2603 2619 Exon18 CAGCTGTTTTAATTCAA 52 7838 7854 3-10-4 668 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 86 7839 7858 5-10-5 317 599024 2604 2620 Exon18 GCAGCTGTTTTAATTCA 88 7839 7855 3-10-4 669 599025 2605 2621 Exon18 CGCAGCTGTTTTAATTC 85 7840 7856 3-10-4 670 599026 2606 2622 Exon18 TCGCAGCTGTTTTAATT 69 7841 7857 3-10-4 671 599027 2607 2623 Exon18 GTCGCAGCTGTTTTAAT 77 7842 7858 3-10-4 672 599028 2608 2624 Exon18 TGTCGCAGCTGTTTTAA 73 7843 7859 3-10-4 673 599029 2609 2625 Exon18 TTGTCGCAGCTGTTTTA 78 7844 7860 3-10-4 674 599030 2610 2626 Exon18 GTTGTCGCAGCTGTTTT 75 7845 7861 3-10-4 675 599031 2611 2627 Exon18 TGTTGTCGCAGCTGTTT 77 7846 7862 3-10-4 676 599032 2612 2628 Exon18/ TTGTTGTCGCAGCTGTT 79 n/a n/a 3-10-4 677 Repeat 599033 2613 2629 Exon18/ TTTGTTGTCGCAGCTGT 80 n/a n/a 3-10-4 678 Repeat 599034 2614 2630 Exon18/ TTTTGTTGTCGCAGCTG 78 n/a n/a 3-10-4 679 Repeat 599035 2615 2631 Exon18/ TTTTTGTTGTCGCAGCT 63 n/a n/a 3-10-4 680 Repeat

TABLE-US-00013 TABLE12 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 599098 2552 2568 Exon18 GAAAACCCAAATCCTCA 57 7787 7803 4-8-5 619 599099 2553 2569 Exon18 AGAAAACCCAAATCCTC 33 7788 7804 4-8-5 620 599100 2554 2570 Exon18 TAGAAAACCCAAATCCT 32 7789 7805 4-8-5 621 599101 2555 2571 Exon18 ATAGAAAACCCAAATCC 47 7790 7806 4-8-5 622 599102 2557 2573 Exon18 TTATAGAAAACCCAAAT 59 7792 7808 4-8-5 623 599103 2558 2574 Exon18 CTTATAGAAAACCCAAA 10 7793 7809 4-8-5 624 599104 2559 2575 Exon18 CCTTATAGAAAACCCAA 3 7794 7810 4-8-5 625 599105 2560 2576 Exon18 CCCTTATAGAAAACCCA 45 7795 7811 4-8-5 626 599106 2561 2577 Exon18 CCCCTTATAGAAAACCC 49 7796 7812 4-8-5 627 599107 2562 2578 Exon18 ACCCCTTATAGAAAACC 35 7797 7813 4-8-5 628 599108 2563 2579 Exon18 AACCCCTTATAGAAAAC 17 7798 7814 4-8-5 629 599109 2564 2580 Exon18 AAACCCCTTATAGAAAA 36 7799 7815 4-8-5 630 599110 2565 2581 Exon18 GAAACCCCTTATAGAAA 20 7800 7816 4-8-5 631 599111 2566 2582 Exon18 GGAAACCCCTTATAGAA 20 7801 7817 4-8-5 632 599112 2567 2583 Exon18 AGGAAACCCCTTATAGA 15 7802 7818 4-8-5 633 599113 2568 2584 Exon18 CAGGAAACCCCTTATAG 19 7803 7819 4-8-5 634 599051 2568 2584 Exon18 CAGGAAACCCCTTATAG 26 7803 7819 5-7-5 634 599114 2569 2585 Exon18 GCAGGAAACCCCTTATA 18 7804 7820 4-8-5 635 599052 2569 2585 Exon18 GCAGGAAACCCCTTATA 21 7804 7820 5-7-5 635 599115 2570 2586 Exon18 AGCAGGAAACCCCTTAT 31 7805 7821 4-8-5 636 599053 2570 2586 Exon18 AGCAGGAAACCCCTTAT 25 7805 7821 5-7-5 636 599116 2571 2587 Exon18 CAGCAGGAAACCCCTTA 39 7806 7822 4-8-5 637 599054 2571 2587 Exon18 CAGCAGGAAACCCCTTA 36 7806 7822 5-7-5 637 599117 2572 2588 Exon18 CCAGCAGGAAACCCCTT 46 7807 7823 4-8-5 638 599055 2572 2588 Exon18 CCAGCAGGAAACCCCTT 22 7807 7823 5-7-5 638 599118 2573 2589 Exon18 TCCAGCAGGAAACCCCT 40 7808 7824 4-8-5 639 599056 2573 2589 Exon18 TCCAGCAGGAAACCCCT 32 7808 7824 5-7-5 639 599119 2574 2590 Exon18 GTCCAGCAGGAAACCCC 50 7809 7825 4-8-5 640 599057 2574 2590 Exon18 GTCCAGCAGGAAACCCC 46 7809 7825 5-7-5 640 599120 2575 2591 Exon18 TGTCCAGCAGGAAACCC 30 7810 7826 4-8-5 641 599058 2575 2591 Exon18 TGTCCAGCAGGAAACCC 52 7810 7826 5-7-5 641 599121 2576 2592 Exon18 CTGTCCAGCAGGAAACC 31 7811 7827 4-8-5 642 599059 2576 2592 Exon18 CTGTCCAGCAGGAAACC 24 7811 7827 5-7-5 642 599122 2577 2593 Exon18 CCTGTCCAGCAGGAAAC 23 7812 7828 4-8-5 643 599060 2577 2593 Exon18 CCTGTCCAGCAGGAAAC 37 7812 7828 5-7-5 643 599123 2578 2594 Exon18 CCCTGTCCAGCAGGAAA 51 7813 7829 4-8-5 644 599061 2578 2594 Exon18 CCCTGTCCAGCAGGAAA 34 7813 7829 5-7-5 644 599124 2580 2596 Exon18 GCCCCTGTCCAGCAGGA 56 7815 7831 4-8-5 645 599062 2580 2596 Exon18 GCCCCTGTCCAGCAGGA 51 7815 7831 5-7-5 645 599125 2581 2597 Exon18 CGCCCCTGTCCAGCAGG 70 7816 7832 4-8-5 646 599063 2581 2597 Exon18 CGCCCCTGTCCAGCAGG 56 7816 7832 5-7-5 646 599126 2582 2598 Exon18 ACGCCCCTGTCCAGCAG 76 7817 7833 4-8-5 647 599064 2582 2598 Exon18 ACGCCCCTGTCCAGCAG 61 7817 7833 5-7-5 647 599127 2583 2599 Exon18 CACGCCCCTGTCCAGCA 67 7818 7834 4-8-5 648 599065 2583 2599 Exon18 CACGCCCCTGTCCAGCA 64 7818 7834 5-7-5 648 599066 2584 2600 Exon18 CCACGCCCCTGTCCAGC 40 7819 7835 5-7-5 649 599067 2585 2601 Exon18 CCCACGCCCCTGTCCAG 37 7820 7836 5-7-5 650 599068 2586 2602 Exon18 TCCCACGCCCCTGTCCA 31 7821 7837 5-7-5 651 599069 2587 2603 Exon18 ATCCCACGCCCCTGTCC 39 7822 7838 5-7-5 652 599070 2588 2604 Exon18 AATCCCACGCCCCTGTC 59 7823 7839 5-7-5 653 599071 2589 2605 Exon18 CAATCCCACGCCCCTGT 63 7824 7840 5-7-5 657 599072 2590 2606 Exon18 TCAATCCCACGCCCCTG 74 7825 7841 5-7-5 655 599073 2591 2607 Exon18 TTCAATCCCACGCCCCT 53 7826 7842 5-7-5 656 599074 2592 2608 Exon18 ATTCAATCCCACGCCCC 56 7827 7843 5-7-5 657 599075 2593 2609 Exon18 AATTCAATCCCACGCCC 49 7828 7844 5-7-5 658 599076 2594 2610 Exon18 TAATTCAATCCCACGCC 54 7829 7845 5-7-5 659 599077 2595 2611 Exon18 TTAATTCAATCCCACGC 79 7830 7846 5-7-5 660 599078 2596 2612 Exon18 TTTAATTCAATCCCACG 67 7831 7847 5-7-5 661 599079 2597 2613 Exon18 TTTTAATTCAATCCCAC 69 7832 7848 5-7-5 662 599080 2598 2614 Exon18 GTTTTAATTCAATCCCA 79 7833 7849 5-7-5 663 599081 2599 2615 Exon18 TGTTTTAATTCAATCCC 57 7834 7850 5-7-5 664 599082 2600 2616 Exon18 CTGTTTTAATTCAATCC 50 7835 7851 5-7-5 665 599083 2601 2617 Exon18 GCTGTTTTAATTCAATC 67 7836 7852 5-7-5 666 599084 2602 2618 Exon18 AGCTGTTTTAATTCAAT 60 7837 7853 5-7-5 667 599085 2603 2619 Exon18 CAGCTGTTTTAATTCAA 71 7838 7854 5-7-5 668 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 82 7839 7858 5-10-5 317 599086 2604 2620 Exon18 GCAGCTGTTTTAATTCA 81 7839 7855 5-7-5 669 599087 2605 2621 Exon18 CGCAGCTGTTTTAATTC 88 7840 7856 5-7-5 670 599088 2606 2622 Exon18 TCGCAGCTGTTTTAATT 84 7841 7857 5-7-5 671 599089 2607 2623 Exon18 GTCGCAGCTGTTTTAAT 81 7842 7858 5-7-5 672 599090 2608 2624 Exon18 TGTCGCAGCTGTTTTAA 77 7843 7859 5-7-5 673 599091 2609 2625 Exon18 TTGTCGCAGCTGTTTTA 74 7844 7860 5-7-5 674 599092 2610 2626 Exon18 GTTGTCGCAGCTGTTTT 66 7845 7861 5-7-5 675 599093 2611 2627 Exon18 TGTTGTCGCAGCTGTTT 89 7846 7862 5-7-5 676 599094 2612 2628 Exon18/ TTGTTGTCGCAGCTGTT 82 n/a n/a 5-7-5 677 Repeat 599095 2613 2629 Exon18/ TTTGTTGTCGCAGCTGT 87 n/a n/a 5-7-5 678 Repeat 599096 2614 2630 Exon18/ TTTTGTTGTCGCAGCTG 85 n/a n/a 5-7-5 679 Repeat 599097 2615 2631 Exon18/ TTTTTGTTGTCGCAGCT 78 n/a n/a 5-7-5 680 Repeat

TABLE-US-00014 TABLE13 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 599510 2552 2570 Exon18 TAGAAAACCCAAATCCTCA 45 7787 7805 5-9-5 681 599331 2553 2571 Exon18 ATAGAAAACCCAAATCCTC 46 7788 7806 5-9-5 682 599332 2554 2572 Exon18 TATAGAAAACCCAAATCCT 38 7789 7807 5-9-5 683 599333 2556 2574 Exon18 CTTATAGAAAACCCAAATC 1 7791 7809 5-9-5 684 599334 2557 2575 Exon18 CCTTATAGAAAACCCAAAT 5 7792 7810 5-9-5 685 599335 2558 2576 Exon18 CCCTTATAGAAAACCCAAA 34 7793 7811 5-9-5 686 599336 2559 2577 Exon18 CCCCTTATAGAAAACCCAA 40 7794 7812 5-9-5 687 599337 2560 2578 Exon18 ACCCCTTATAGAAAACCCA 39 7795 7813 5-9-5 688 599338 2561 2579 Exon18 AACCCCTTATAGAAAACCC 57 7796 7814 5-9-5 689 599339 2562 2580 Exon18 AAACCCCTTATAGAAAACC 26 7797 7815 5-9-5 690 599281 2562 2580 Exon18 AAACCCCTTATAGAAAACC 15 7797 7815 6-7-6 690 599340 2563 2581 Exon18 GAAACCCCTTATAGAAAAC 17 7798 7816 5-9-5 691 599282 2563 2581 Exon18 GAAACCCCTTATAGAAAAC 12 7798 7816 6-7-6 691 599341 2564 2582 Exon18 GGAAACCCCTTATAGAAAA 23 7799 7817 5-9-5 692 599283 2564 2582 Exon18 GGAAACCCCTTATAGAAAA 18 7799 7817 6-7-6 692 599342 2565 2583 Exon18 AGGAAACCCCTTATAGAAA 10 7800 7818 5-9-5 693 599284 2565 2583 Exon18 AGGAAACCCCTTATAGAAA 14 7800 7818 6-7-6 693 599343 2566 2584 Exon18 CAGGAAACCCCTTATAGAA 10 7801 7819 5-9-5 694 599285 2566 2584 Exon18 CAGGAAACCCCTTATAGAA 13 7801 7819 6-7-6 694 599344 2567 2585 Exon18 GCAGGAAACCCCTTATAGA 22 7802 7820 5-9-5 695 599286 2567 2585 Exon18 GCAGGAAACCCCTTATAGA 31 7802 7820 6-7-6 695 599345 2568 2586 Exon18 AGCAGGAAACCCCTTATAG 19 7803 7821 5-9-5 696 599287 2568 2586 Exon18 AGCAGGAAACCCCTTATAG 12 7803 7821 6-7-6 696 599346 2569 2587 Exon18 CAGCAGGAAACCCCTTATA 30 7804 7822 5-9-5 697 599288 2569 2587 Exon18 CAGCAGGAAACCCCTTATA 28 7804 7822 6-7-6 697 599347 2570 2588 Exon18 CCAGCAGGAAACCCCTTAT 46 7805 7823 5-9-5 698 599289 2570 2588 Exon18 CCAGCAGGAAACCCCTTAT 32 7805 7823 6-7-6 698 599348 2571 2589 Exon18 TCCAGCAGGAAACCCCTTA 44 7806 7824 5-9-5 699 599290 2571 2589 Exon18 TCCAGCAGGAAACCCCTTA 24 7806 7824 6-7-6 699 599349 2572 2590 Exon18 GTCCAGCAGGAAACCCCTT 60 7807 7825 5-9-5 700 599291 2572 2590 Exon18 GTCCAGCAGGAAACCCCTT 38 7807 7825 6-7-6 700 599350 2573 2591 Exon18 TGTCCAGCAGGAAACCCCT 49 7808 7826 5-9-5 701 599292 2573 2591 Exon18 TGTCCAGCAGGAAACCCCT 35 7808 7826 6-7-6 701 599351 2575 2593 Exon18 CCTGTCCAGCAGGAAACCC 46 7810 7828 5-9-5 702 599293 2575 2593 Exon18 CCTGTCCAGCAGGAAACCC 12 7810 7828 6-7-6 702 599352 2576 2594 Exon18 CCCTGTCCAGCAGGAAACC 49 7811 7829 5-9-5 703 599294 2576 2594 Exon18 CCCTGTCCAGCAGGAAACC 38 7811 7829 6-7-6 703 599353 2577 2595 Exon18 CCCCTGTCCAGCAGGAAAC 64 7812 7830 5-9-5 704 599295 2577 2595 Exon18 CCCCTGTCCAGCAGGAAAC 33 7812 7830 6-7-6 704 599354 2578 2596 Exon18 GCCCCTGTCCAGCAGGAAA 56 7813 7831 5-9-5 705 599296 2578 2596 Exon18 GCCCCTGTCCAGCAGGAAA 13 7813 7831 6-7-6 705 599355 2580 2598 Exon18 ACGCCCCTGTCCAGCAGGA 81 7815 7833 5-9-5 706 599297 2580 2598 Exon18 ACGCCCCTGTCCAGCAGGA 57 7815 7833 6-7-6 706 599356 2581 2599 Exon18 CACGCCCCTGTCCAGCAGG 64 7816 7834 5-9-5 707 599298 2581 2599 Exon18 CACGCCCCTGTCCAGCAGG 39 7816 7834 6-7-6 707 599299 2582 2600 Exon18 CCACGCCCCTGTCCAGCAG 55 7817 7835 6-7-6 708 599300 2583 2601 Exon18 CCCACGCCCCTGTCCAGCA 45 7818 7836 6-7-6 709 599301 2584 2602 Exon18 TCCCACGCCCCTGTCCAGC 39 7819 7837 6-7-6 710 599302 2585 2603 Exon18 ATCCCACGCCCCTGTCCAG 27 7820 7838 6-7-6 711 599303 2586 2604 Exon18 AATCCCACGCCCCTGTCCA 35 7821 7839 6-7-6 712 599304 2587 2605 Exon18 CAATCCCACGCCCCTGTCC 16 7822 7840 6-7-6 713 599305 2588 2606 Exon18 TCAATCCCACGCCCCTGTC 41 7823 7841 6-7-6 714 599306 2589 2607 Exon18 TTCAATCCCACGCCCCTGT 70 7824 7842 6-7-6 715 599307 2590 2608 Exon18 ATTCAATCCCACGCCCCTG 66 7825 7843 6-7-6 716 599308 2591 2609 Exon18 AATTCAATCCCACGCCCCT 68 7826 7844 6-7-6 717 599309 2592 2610 Exon18 TAATTCAATCCCACGCCCC 52 7827 7845 6-7-6 718 599310 2593 2611 Exon18 TTAATTCAATCCCACGCCC 39 7828 7846 6-7-6 719 599311 2594 2612 Exon18 TTTAATTCAATCCCACGCC 83 7829 7847 6-7-6 720 599312 2595 2613 Exon18 TTTTAATTCAATCCCACGC 72 7830 7848 6-7-6 721 599313 2596 2614 Exon18 GTTTTAATTCAATCCCACG 86 7831 7849 6-7-6 722 599314 2597 2615 Exon18 TGTTTTAATTCAATCCCAC 91 7832 7850 6-7-6 723 599315 2598 2616 Exon18 CTGTTTTAATTCAATCCCA 71 7833 7851 6-7-6 724 599316 2599 2617 Exon18 GCTGTTTTAATTCAATCCC 89 7834 7852 6-7-6 725 599317 2600 2618 Exon18 AGCTGTTTTAATTCAATCC 87 7835 7853 6-7-6 726 599318 2601 2619 Exon18 CAGCTGTTTTAATTCAATC 81 7836 7854 6-7-6 727 599319 2602 2620 Exon18 GCAGCTGTTTTAATTCAAT 75 7837 7855 6-7-6 728 599320 2603 2621 Exon18 CGCAGCTGTTTTAATTCAA 84 7838 7856 6-7-6 729 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 92 7839 7858 5-10-5 317 599321 2604 2622 Exon18 TCGCAGCTGTTTTAATTCA 90 7839 7857 6-7-6 730 599322 2605 2623 Exon18 GTCGCAGCTGTTTTAATTC 89 7840 7858 6-7-6 731 599323 2606 2624 Exon18 TGTCGCAGCTGTTTTAATT 81 7841 7859 6-7-6 732 599324 2607 2625 Exon18 TTGTCGCAGCTGTTTTAAT 68 7842 7860 6-7-6 733 599325 2608 2626 Exon18 GTTGTCGCAGCTGTTTTAA 71 7843 7861 6-7-6 734 599326 2609 2627 Exon18 TGTTGTCGCAGCTGTTTTA 52 7844 7862 6-7-6 735 599327 2610 2628 Exon18/ TTGTTGTCGCAGCTGTTTT 88 n/a n/a 6-7-6 736 Repeat 599328 2611 2629 Exon18/ TTTGTTGTCGCAGCTGTTT 87 n/a n/a 6-7-6 737 Repeat 599329 2612 2630 Exon18/ TTTTGTTGTCGCAGCTGTT 84 n/a n/a 6-7-6 738 Repeat 599330 2613 2631 Exon18/ TTTTTGTTGTCGCAGCTGT 87 n/a n/a 6-7-6 739 Repeat

TABLE-US-00015 TABLE14 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 599512 2552 2571 Exon18 ATAGAAAACCCAAATCCTCA 74 7787 7806 3-10-7 410 599449 2553 2572 Exon18 TATAGAAAACCCAAATCCTC 43 7788 7807 3-10-7 411 599450 2554 2573 Exon18 TTATAGAAAACCCAAATCCT 51 7789 7808 3-10-7 412 599451 2555 2574 Exon18 CTTATAGAAAACCCAAATCC 35 7790 7809 3-10-7 413 599452 2556 2575 Exon18 CCTTATAGAAAACCCAAATC 34 7791 7810 3-10-7 414 599453 2557 2576 Exon18 CCCTTATAGAAAACCCAAAT 44 7792 7811 3-10-7 415 599454 2558 2577 Exon18 CCCCTTATAGAAAACCCAAA 54 7793 7812 3-10-7 416 599455 2559 2578 Exon18 ACCCCTTATAGAAAACCCAA 53 7794 7813 3-10-7 417 599456 2560 2579 Exon18 AACCCCTTATAGAAAACCCA 69 7795 7814 3-10-7 418 599457 2561 2580 Exon18 AAACCCCTTATAGAAAACCC 46 7796 7815 3-10-7 419 599458 2562 2581 Exon18 GAAACCCCTTATAGAAAACC 0 7797 7816 3-10-7 420 599459 2563 2582 Exon18 GGAAACCCCTTATAGAAAAC 12 7798 7817 3-10-7 421 599460 2564 2583 Exon18 AGGAAACCCCTTATAGAAAA 17 7799 7818 3-10-7 422 599461 2565 2584 Exon18 CAGGAAACCCCTTATAGAAA 24 7800 7819 3-10-7 423 599462 2566 2585 Exon18 GCAGGAAACCCCTTATAGAA 33 7801 7820 3-10-7 424 599463 2567 2586 Exon18 AGCAGGAAACCCCTTATAGA 38 7802 7821 3-10-7 425 599464 2568 2587 Exon18 CAGCAGGAAACCCCTTATAG 33 7803 7822 3-10-7 426 599465 2569 2588 Exon18 CCAGCAGGAAACCCCTTATA 49 7804 7823 3-10-7 427 599466 2570 2589 Exon18 TCCAGCAGGAAACCCCTTAT 45 7805 7824 3-10-7 428 599467 2571 2590 Exon18 GTCCAGCAGGAAACCCCTTA 60 7806 7825 3-10-7 237 599468 2572 2591 Exon18 TGTCCAGCAGGAAACCCCTT 61 7807 7826 3-10-7 429 599469 2573 2592 Exon18 CTGTCCAGCAGGAAACCCCT 52 7808 7827 3-10-7 430 599470 2574 2593 Exon18 CCTGTCCAGCAGGAAACCCC 45 7809 7828 3-10-7 431 599471 2575 2594 Exon18 CCCTGTCCAGCAGGAAACCC 67 7810 7829 3-10-7 432 599472 2576 2595 Exon18 CCCCTGTCCAGCAGGAAACC 79 7811 7830 3-10-7 433 599473 2577 2596 Exon18 GCCCCTGTCCAGCAGGAAAC 72 7812 7831 3-10-7 238 599474 2578 2597 Exon18 CGCCCCTGTCCAGCAGGAAA 87 7813 7832 3-10-7 434 599475 2579 2598 Exon18 ACGCCCCTGTCCAGCAGGAA 76 7814 7833 3-10-7 435 599476 2580 2599 Exon18 CACGCCCCTGTCCAGCAGGA 81 7815 7834 3-10-7 436 599477 2581 2600 Exon18 CCACGCCCCTGTCCAGCAGG 83 7816 7835 3-10-7 437 599478 2582 2601 Exon18 CCCACGCCCCTGTCCAGCAG 72 7817 7836 3-10-7 438 599479 2583 2602 Exon18 TCCCACGCCCCTGTCCAGCA 81 7818 7837 3-10-7 439 599480 2584 2603 Exon18 ATCCCACGCCCCTGTCCAGC 77 7819 7838 3-10-7 440 599481 2585 2604 Exon18 AATCCCACGCCCCTGTCCAG 83 7820 7839 3-10-7 441 599482 2586 2605 Exon18 CAATCCCACGCCCCTGTCCA 87 7821 7840 3-10-7 442 599483 2587 2606 Exon18 TCAATCCCACGCCCCTGTCC 90 7822 7841 3-10-7 443 599484 2588 2607 Exon18 TTCAATCCCACGCCCCTGTC 72 7823 7842 3-10-7 444 599485 2589 2608 Exon18 ATTCAATCCCACGCCCCTGT 82 7824 7843 3-10-7 445 599486 2590 2609 Exon18 AATTCAATCCCACGCCCCTG 84 7825 7844 3-10-7 446 599487 2591 2610 Exon18 TAATTCAATCCCACGCCCCT 84 7826 7845 3-10-7 447 599488 2592 2611 Exon18 TTAATTCAATCCCACGCCCC 87 7827 7846 3-10-7 448 599489 2593 2612 Exon18 TTTAATTCAATCCCACGCCC 87 7828 7847 3-10-7 449 599490 2594 2613 Exon18 TTTTAATTCAATCCCACGCC 86 7829 7848 3-10-7 450 599491 2595 2614 Exon18 GTTTTAATTCAATCCCACGC 87 7830 7849 3-10-7 451 599492 2596 2615 Exon18 TGTTTTAATTCAATCCCACG 88 7831 7850 3-10-7 452 599493 2597 2616 Exon18 CTGTTTTAATTCAATCCCAC 75 7832 7851 3-10-7 453 599433 2597 2616 Exon18 CTGTTTTAATTCAATCCCAC 89 7832 7851 6-8-6 453 599494 2598 2617 Exon18 GCTGTTTTAATTCAATCCCA 90 7833 7852 3-10-7 454 599434 2598 2617 Exon18 GCTGTTTTAATTCAATCCCA 89 7833 7852 6-8-6 454 599495 2599 2618 Exon18 AGCTGTTTTAATTCAATCCC 88 7834 7853 3-10-7 239 599435 2599 2618 Exon18 AGCTGTTTTAATTCAATCCC 91 7834 7853 6-8-6 239 599496 2600 2619 Exon18 CAGCTGTTTTAATTCAATCC 89 7835 7854 3-10-7 455 599436 2600 2619 Exon18 CAGCTGTTTTAATTCAATCC 89 7835 7854 6-8-6 455 599497 2601 2620 Exon18 GCAGCTGTTTTAATTCAATC 89 7836 7855 3-10-7 456 599437 2601 2620 Exon18 GCAGCTGTTTTAATTCAATC 91 7836 7855 6-8-6 456 599498 2602 2621 Exon18 CGCAGCTGTTTTAATTCAAT 88 7837 7856 3-10-7 457 599438 2602 2621 Exon18 CGCAGCTGTTTTAATTCAAT 90 7837 7856 6-8-6 457 599499 2603 2622 Exon18 TCGCAGCTGTTTTAATTCAA 81 7838 7857 3-10-7 458 599439 2603 2622 Exon18 TCGCAGCTGTTTTAATTCAA 88 7838 7857 6-8-6 458 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 90 7839 7858 5-10-5 317 599500 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 88 7839 7858 3-10-7 317 599440 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 88 7839 7858 6-8-6 317 599501 2605 2624 Exon18 TGTCGCAGCTGTTTTAATTC 78 7840 7859 3-10-7 459 599441 2605 2624 Exon18 TGTCGCAGCTGTTTTAATTC 90 7840 7859 6-8-6 459 599502 2606 2625 Exon18 TTGTCGCAGCTGTTTTAATT 87 7841 7860 3-10-7 460 599442 2606 2625 Exon18 TTGTCGCAGCTGTTTTAATT 76 7841 7860 6-8-6 460 599503 2607 2626 Exon18 GTTGTCGCAGCTGTTTTAAT 83 7842 7861 3-10-7 461 599443 2607 2626 Exon18 GTTGTCGCAGCTGTTTTAAT 77 7842 7861 6-8-6 461 599504 2608 2627 Exon18 TGTTGTCGCAGCTGTTTTAA 89 7843 7862 3-10-7 395 599444 2608 2627 Exon18 TGTTGTCGCAGCTGTTTTAA 69 7843 7862 6-8-6 395 599505 2609 2628 Exon19/ TTGTTGTCGCAGCTGTTTTA 83 n/a n/a 3-10-7 462 Repeat 599445 2609 2628 Exon19/ TTGTTGTCGCAGCTGTTTTA 85 n/a n/a 6-8-6 462 Repeat 599506 2610 2629 Exon19/ TTTGTTGTCGCAGCTGTTTT 89 n/a n/a 3-10-7 463 Repeat 599446 2610 2629 Exon19/ TTTGTTGTCGCAGCTGTTTT 85 n/a n/a 6-8-6 463 Repeat 599507 2611 2630 Exon19/ TTTTGTTGTCGCAGCTGTTT 82 n/a n/a 3-10-7 464 Repeat 599447 2611 2630 Exon19/ TTTTGTTGTCGCAGCTGTTT 83 n/a n/a 6-8-6 464 Repeat 599508 2612 2631 Exon19/ TTTTTGTTGTCGCAGCTGTT 90 n/a n/a 3-10-7 465 Repeat 599448 2612 2631 Exon19/ TTTTTGTTGTCGCAGCTGTT 87 n/a n/a 6-8-6 465 Repeat

Example 5: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells by MOE Gapmers

[0447] Additional antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 2,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0448] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as 4-8-5 MOE, 5-8-5 MOE, 5-9-5 MOE, 5-10-5 MOE, 6-7-6-MOE, 3-10-5 MOE, or 6-8-6 MOE gapmers.

[0449] The 4-8-5 MOE gapmers are 17 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising four and five nucleosides respectively. The 5-8-5 MOE gapmers are 18 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 5-9-5 MOE gapmers are 19 nucleosides in length, wherein the central gap segment comprises of nine 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 5-10-5 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 3-10-5 MOE gapmers are 18 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising three and five nucleosides respectively. The 6-7-6 MOE gapmers are 19 nucleosides in length, wherein the central gap segment comprises of seven 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising six nucleosides each. The 6-8-6 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising six nucleosides each. Each nucleoside in the 5 wing segment and each nucleoside in the 3 wing segment has a 2-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

[0450] Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity.

TABLE-US-00016 TABLE15 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 599160 2560 2577 Exon18 CCCCTTATAGAAAACCCA 26 7795 7812 5-8-5 740 599161 2561 2578 Exon18 ACCCCTTATAGAAAACCC 20 7796 7813 5-8-5 741 599162 2562 2579 Exon18 AACCCCTTATAGAAAACC 12 7797 7814 5-8-5 742 599163 2563 2580 Exon18 AAACCCCTTATAGAAAAC 11 7798 7815 5-8-5 743 599164 2564 2581 Exon18 GAAACCCCTTATAGAAAA 11 7799 7816 5-8-5 744 599165 2566 2583 Exon18 AGGAAACCCCTTATAGAA 0 7801 7818 5-8-5 745 599166 2567 2584 Exon18 CAGGAAACCCCTTATAGA 12 7802 7819 5-8-5 746 599167 2568 2585 Exon18 GCAGGAAACCCCTTATAG 14 7803 7820 5-8-5 747 599168 2569 2586 Exon18 AGCAGGAAACCCCTTATA 16 7804 7821 5-8-5 748 599169 2570 2587 Exon18 CAGCAGGAAACCCCTTAT 24 7805 7822 5-8-5 749 599170 2571 2588 Exon18 CCAGCAGGAAACCCCTTA 37 7806 7823 5-8-5 750 599171 2572 2589 Exon18 TCCAGCAGGAAACCCCTT 30 7807 7824 5-8-5 751 599172 2573 2590 Exon18 GTCCAGCAGGAAACCCCT 43 7808 7825 5-8-5 752 599173 2574 2591 Exon18 TGTCCAGCAGGAAACCCC 47 7809 7826 5-8-5 753 599174 2575 2592 Exon18 CTGTCCAGCAGGAAACCC 27 7810 7827 5-8-5 754 599175 2576 2593 Exon18 CCTGTCCAGCAGGAAACC 30 7811 7828 5-8-5 755 599176 2577 2594 Exon18 CCCTGTCCAGCAGGAAAC 34 7812 7829 5-8-5 756 599177 2578 2595 Exon18 CCCCTGTCCAGCAGGAAA 41 7813 7830 5-8-5 757 599178 2580 2597 Exon18 CGCCCCTGTCCAGCAGGA 67 7815 7832 5-8-5 758 599179 2581 2598 Exon18 ACGCCCCTGTCCAGCAGG 61 7816 7833 5-8-5 759 599180 2582 2599 Exon18 CACGCCCCTGTCCAGCAG 62 7817 7834 5-8-5 760 599181 2583 2600 Exon18 CCACGCCCCTGTCCAGCA 63 7818 7835 5-8-5 761 599128 2584 2600 Exon18 CCACGCCCCTGTCCAGC 55 7819 7835 4-8-5 649 599182 2584 2601 Exon18 CCCACGCCCCTGTCCAGC 58 7819 7836 5-8-5 762 599129 2585 2601 Exon18 CCCACGCCCCTGTCCAG 41 7820 7836 4-8-5 650 599183 2585 2602 Exon18 TCCCACGCCCCTGTCCAG 43 7820 7837 5-8-5 763 599130 2586 2602 Exon18 TCCCACGCCCCTGTCCA 46 7821 7837 4-8-5 651 599184 2586 2603 Exon18 ATCCCACGCCCCTGTCCA 32 7821 7838 5-8-5 764 599131 2587 2603 Exon18 ATCCCACGCCCCTGTCC 30 7822 7838 4-8-5 652 599185 2587 2604 Exon18 AATCCCACGCCCCTGTCC 35 7822 7839 5-8-5 765 599132 2588 2604 Exon18 AATCCCACGCCCCTGTC 52 7823 7839 4-8-5 653 599186 2588 2605 Exon18 CAATCCCACGCCCCTGTC 55 7823 7840 5-8-5 766 599133 2589 2605 Exon18 CAATCCCACGCCCCTGT 66 7824 7840 4-8-5 654 599187 2589 2606 Exon18 TCAATCCCACGCCCCTGT 72 7824 7841 5-8-5 767 599134 2590 2606 Exon18 TCAATCCCACGCCCCTG 80 7825 7841 4-8-5 655 599188 2590 2607 Exon18 TTCAATCCCACGCCCCTG 92 7825 7842 5-8-5 768 599135 2591 2607 Exon18 TTCAATCCCACGCCCCT 61 7826 7842 4-8-5 656 599189 2591 2608 Exon18 ATTCAATCCCACGCCCCT 52 7826 7843 5-8-5 769 599136 2592 2608 Exon18 ATTCAATCCCACGCCCC 68 7827 7843 4-8-5 657 599190 2592 2609 Exon18 AATTCAATCCCACGCCCC 62 7827 7844 5-8-5 770 599137 2593 2609 Exon18 AATTCAATCCCACGCCC 51 7828 7844 4-8-5 658 599191 2593 2610 Exon18 TAATTCAATCCCACGCCC 54 7828 7845 5-8-5 771 599138 2594 2610 Exon18 TAATTCAATCCCACGCC 71 7829 7845 4-8-5 659 599192 2594 2611 Exon18 TTAATTCAATCCCACGCC 66 7829 7846 5-8-5 772 599139 2595 2611 Exon18 TTAATTCAATCCCACGC 80 7830 7846 4-8-5 660 599193 2595 2612 Exon18 TTTAATTCAATCCCACGC 74 7830 7847 5-8-5 773 599140 2596 2612 Exon18 TTTAATTCAATCCCACG 66 7831 7847 4-8-5 786 599194 2596 2613 Exon18 TTTTAATTCAATCCCACG 66 7831 7848 5-8-5 774 599141 2597 2613 Exon18 TTTTAATTCAATCCCAC 63 7832 7848 4-8-5 662 599195 2597 2614 Exon18 GTTTTAATTCAATCCCAC 86 7832 7849 5-8-5 775 599142 2598 2614 Exon18 GTTTTAATTCAATCCCA 69 7833 7849 4-8-5 663 599196 2598 2615 Exon18 TGTTTTAATTCAATCCCA 82 7833 7850 5-8-5 776 599143 2599 2615 Exon18 TGTTTTAATTCAATCCC 59 7834 7850 4-8-5 664 599197 2599 2616 Exon18 CTGTTTTAATTCAATCCC 79 7834 7851 5-8-5 777 599144 2600 2616 Exon18 CTGTTTTAATTCAATCC 52 7835 7851 4-8-5 665 599198 2600 2617 Exon18 GCTGTTTTAATTCAATCC 86 7835 7852 5-8-5 778 599145 2601 2617 Exon18 GCTGTTTTAATTCAATC 53 7836 7852 4-8-5 666 599199 2601 2618 Exon18 AGCTGTTTTAATTCAATC 72 7836 7853 5-8-5 779 599146 2602 2618 Exon18 AGCTGTTTTAATTCAAT 42 7837 7853 4-8-5 667 599200 2602 2619 Exon18 CAGCTGTTTTAATTCAAT 76 7837 7854 5-8-5 780 599147 2603 2619 Exon18 CAGCTGTTTTAATTCAA 55 7838 7854 4-8-5 668 599201 2603 2620 Exon18 GCAGCTGTTTTAATTCAA 87 7838 7855 5-8-5 781 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 93 7839 7858 5-10-5 317 599148 2604 2620 Exon18 GCAGCTGTTTTAATTCA 84 7839 7855 4-8-5 669 599202 2604 2621 Exon18 CGCAGCTGTTTTAATTCA 89 7839 7856 5-8-5 782 599149 2605 2621 Exon18 CGCAGCTGTTTTAATTC 92 7840 7856 4-8-5 670 599203 2605 2622 Exon18 TCGCAGCTGTTTTAATTC 90 7840 7857 5-8-5 783 599150 2606 2622 Exon18 TCGCAGCTGTTTTAATT 75 7841 7857 4-8-5 671 599151 2607 2623 Exon18 GTCGCAGCTGTTTTAAT 80 7842 7858 4-8-5 672 599152 2608 2624 Exon18 TGTCGCAGCTGTTTTAA 76 7843 7859 4-8-5 673 599153 2609 2625 Exon18 TTGTCGCAGCTGTTTTA 56 7844 7860 4-8-5 674 599154 2610 2626 Exon18 GTTGTCGCAGCTGTTTT 85 7845 7861 4-8-5 675 599155 2611 2627 Exon18 TGTTGTCGCAGCTGTTT 89 7846 7862 4-8-5 676 599156 2612 2628 Exon18/ TTGTTGTCGCAGCTGTT 83 n/a n/a 4-8-5 813 Repeat 599157 2613 2629 Exon18/ TTTGTTGTCGCAGCTGT 78 n/a n/a 4-8-5 678 Repeat 599158 2614 2630 Exon18/ TTTTGTTGTCGCAGCTG 83 n/a n/a 4-8-5 679 Repeat 599159 2615 2631 Exon18/ TTTTTGTTGTCGCAGCT 65 n/a n/a 4-8-5 680 Repeat 599204 2606 2623 Exon18 GTCGCAGCTGTTTTAATT 83 7841 7858 5-8-5 784

TABLE-US-00017 TABLE16 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 599509 2552 2570 Exon18 TAGAAAACCCAAATCCTCA 45 7787 7805 6-7-6 681 599213 2553 2570 Exon18 TAGAAAACCCAAATCCTC 89 7788 7805 3-10-5 785 599273 2553 2571 Exon18 ATAGAAAACCCAAATCCTC 85 7788 7806 6-7-6 682 599214 2554 2571 Exon18 ATAGAAAACCCAAATCCT 79 7789 7806 3-10-5 786 599274 2554 2572 Exon18 TATAGAAAACCCAAATCCT 75 7789 7807 6-7-6 683 599215 2555 2572 Exon18 TATAGAAAACCCAAATCC 81 7790 7807 3-10-5 787 599216 2556 2573 Exon18 TTATAGAAAACCCAAATC 87 7791 7808 3-10-5 788 599275 2556 2574 Exon18 CTTATAGAAAACCCAAATC 84 7791 7809 6-7-6 684 599217 2557 2574 Exon18 CTTATAGAAAACCCAAAT 84 7792 7809 3-10-5 789 599276 2557 2575 Exon18 CCTTATAGAAAACCCAAAT 68 7792 7810 6-7-6 685 599218 2558 2575 Exon18 CCTTATAGAAAACCCAAA 82 7793 7810 3-10-5 790 599277 2558 2576 Exon18 CCCTTATAGAAAACCCAAA 82 7793 7811 6-7-6 686 599219 2559 2576 Exon18 CCCTTATAGAAAACCCAA 81 7794 7811 3-10-5 791 599278 2559 2577 Exon18 CCCCTTATAGAAAACCCAA 84 7794 7812 6-7-6 687 599220 2560 2577 Exon18 CCCCTTATAGAAAACCCA 92 7795 7812 3-10-5 740 599279 2560 2578 Exon18 ACCCCTTATAGAAAACCCA 92 7795 7813 6-7-6 688 599221 2561 2578 Exon18 ACCCCTTATAGAAAACCC 93 7796 7813 3-10-5 741 599280 2561 2579 Exon18 AACCCCTTATAGAAAACCC 90 7796 7814 6-7-6 689 599222 2562 2579 Exon18 AACCCCTTATAGAAAACC 95 7797 7814 3-10-5 742 599223 2563 2580 Exon18 AAACCCCTTATAGAAAAC 93 7798 7815 3-10-5 743 599224 2564 2581 Exon18 GAAACCCCTTATAGAAAA 90 7799 7816 3-10-5 744 599225 2566 2583 Exon18 AGGAAACCCCTTATAGAA 93 7801 7818 3-10-5 745 599226 2567 2584 Exon18 CAGGAAACCCCTTATAGA 95 7802 7819 3-10-5 746 599227 2568 2585 Exon18 GCAGGAAACCCCTTATAG 94 7803 7820 3-10-5 747 599228 2569 2586 Exon18 AGCAGGAAACCCCTTATA 96 7804 7821 3-10-5 748 599229 2570 2587 Exon18 CAGCAGGAAACCCCTTAT 92 7805 7822 3-10-5 749 599230 2571 2588 Exon18 CCAGCAGGAAACCCCTTA 88 7806 7823 3-10-5 750 599231 2572 2589 Exon18 TCCAGCAGGAAACCCCTT 83 7807 7824 3-10-5 751 599232 2573 2590 Exon18 GTCCAGCAGGAAACCCCT 89 7808 7825 3-10-5 752 599233 2574 2591 Exon18 TGTCCAGCAGGAAACCCC 83 7809 7826 3-10-5 753 599234 2575 2592 Exon18 CTGTCCAGCAGGAAACCC 88 7810 7827 3-10-5 754 599235 2576 2593 Exon18 CCTGTCCAGCAGGAAACC 91 7811 7828 3-10-5 755 599236 2577 2594 Exon18 CCCTGTCCAGCAGGAAAC 90 7812 7829 3-10-5 756 599237 2578 2595 Exon18 CCCCTGTCCAGCAGGAAA 34 7813 7830 3-10-5 757 599238 2580 2597 Exon18 CGCCCCTGTCCAGCAGGA 14 7815 7832 3-10-5 758 599239 2581 2598 Exon18 ACGCCCCTGTCCAGCAGG 10 7816 7833 3-10-5 759 599240 2582 2599 Exon18 CACGCCCCTGTCCAGCAG 26 7817 7834 3-10-5 760 599241 2583 2600 Exon18 CCACGCCCCTGTCCAGCA 11 7818 7835 3-10-5 761 599242 2584 2601 Exon18 CCCACGCCCCTGTCCAGC 24 7819 7836 3-10-5 762 599243 2585 2602 Exon18 TCCCACGCCCCTGTCCAG 23 7820 7837 3-10-5 763 599244 2586 2603 Exon18 ATCCCACGCCCCTGTCCA 29 7821 7838 3-10-5 764 599245 2587 2604 Exon18 AATCCCACGCCCCTGTCC 11 7822 7839 3-10-5 765 599246 2588 2605 Exon18 CAATCCCACGCCCCTGTC 0 7823 7840 3-10-5 766 599247 2589 2606 Exon18 TCAATCCCACGCCCCTGT 21 7824 7841 3-10-5 767 599248 2590 2607 Exon18 TTCAATCCCACGCCCCTG 0 7825 7842 3-10-5 768 599249 2591 2608 Exon18 ATTCAATCCCACGCCCCT 9 7826 7843 3-10-5 769 599250 2592 2609 Exon18 AATTCAATCCCACGCCCC 4 7827 7844 3-10-5 770 599251 2593 2610 Exon18 TAATTCAATCCCACGCCC 12 7828 7845 3-10-5 771 599252 2594 2611 Exon18 TTAATTCAATCCCACGCC 2 7829 7846 3-10-5 772 599253 2595 2612 Exon18 TTTAATTCAATCCCACGC 28 7830 7847 3-10-5 773 599254 2596 2613 Exon18 TTTTAATTCAATCCCACG 27 7831 7848 3-10-5 774 599255 2597 2614 Exon18 GTTTTAATTCAATCCCAC 38 7832 7849 3-10-5 775 599256 2598 2615 Exon18 TGTTTTAATTCAATCCCA 36 7833 7850 3-10-5 776 599257 2599 2616 Exon18 CTGTTTTAATTCAATCCC 48 7834 7851 3-10-5 777 599258 2600 2617 Exon18 GCTGTTTTAATTCAATCC 19 7835 7852 3-10-5 778 599259 2601 2618 Exon18 AGCTGTTTTAATTCAATC 36 7836 7853 3-10-5 779 599260 2602 2619 Exon18 CAGCTGTTTTAATTCAAT 58 7837 7854 3-10-5 780 599261 2603 2620 Exon18 GCAGCTGTTTTAATTCAA 35 7838 7855 3-10-5 781 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 96 7839 7858 5-10-5 317 599262 2604 2621 Exon18 CGCAGCTGTTTTAATTCA 52 7839 7856 3-10-5 782 599263 2605 2622 Exon18 TCGCAGCTGTTTTAATTC 66 7840 7857 3-10-5 783 599264 2606 2623 Exon18 GTCGCAGCTGTTTTAATT 48 7841 7858 3-10-5 784 599265 2607 2624 Exon18 TGTCGCAGCTGTTTTAAT 46 7842 7859 3-10-5 792 599205 2607 2624 Exon18 TGTCGCAGCTGTTTTAAT 83 7842 7859 5-8-5 792 599266 2608 2625 Exon18 TTGTCGCAGCTGTTTTAA 76 7843 7860 3-10-5 793 599206 2608 2625 Exon18 TTGTCGCAGCTGTTTTAA 90 7843 7860 5-8-5 793 599267 2609 2626 Exon18 GTTGTCGCAGCTGTTTTA 53 7844 7861 3-10-5 794 599207 2609 2626 Exon18 GTTGTCGCAGCTGTTTTA 82 7844 7861 5-8-5 794 599268 2610 2627 Exon18 TGTTGTCGCAGCTGTTTT 58 7845 7862 3-10-5 795 599208 2610 2627 Exon18 TGTTGTCGCAGCTGTTTT 70 7845 7862 5-8-5 795 599269 2611 2628 Exon18/ TTGTTGTCGCAGCTGTTT 38 n/a n/a 3-10-5 796 Repeat 599209 2611 2628 Exon18/ TTGTTGTCGCAGCTGTTT 50 n/a n/a 5-8-5 796 Repeat 599270 2612 2629 Exon18/ TTTGTTGTCGCAGCTGTT 46 n/a n/a 3-10-5 797 Repeat 599210 2612 2629 Exon18/ TTTGTTGTCGCAGCTGTT 76 n/a n/a 5-8-5 797 Repeat 599271 2613 2630 Exon18/ TTTTGTTGTCGCAGCTGT 64 n/a n/a 3-10-5 798 Repeat 599211 2613 2630 Exon18/ TTTTGTTGTCGCAGCTGT 78 n/a n/a 5-8-5 798 Repeat 599272 2614 2631 Exon18/ TTTTTGTTGTCGCAGCTG 89 n/a n/a 3-10-5 799 Repeat 599212 2614 2631 Exon18/ TTTTTGTTGTCGCAGCTG 84 n/a n/a 5-8-5 799 Repeat

TABLE-US-00018 TABLE17 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQID SEQID SEQID SEQID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 599511 2552 2571 Exon18 ATAGAAAACCCAAATCCTCA 38 7787 7806 6-8-6 410 599389 2553 2572 Exon18 TATAGAAAACCCAAATCCTC 80 7788 7807 6-8-6 411 599390 2554 2573 Exon18 TTATAGAAAACCCAAATCCT 92 7789 7808 6-8-6 412 599391 2555 2574 Exon18 CTTATAGAAAACCCAAATCC 90 7790 7809 6-8-6 413 599392 2556 2575 Exon18 CCTTATAGAAAACCCAAATC 87 7791 7810 6-8-6 414 599393 2557 2576 Exon18 CCCTTATAGAAAACCCAAAT 87 7792 7811 6-8-6 415 599394 2558 2577 Exon18 CCCCTTATAGAAAACCCAAA 74 7793 7812 6-8-6 416 599395 2559 2578 Exon18 ACCCCTTATAGAAAACCCAA 78 7794 7813 6-8-6 417 599396 2560 2579 Exon18 AACCCCTTATAGAAAACCCA 77 7795 7814 6-8-6 418 599397 2561 2580 Exon18 AAACCCCTTATAGAAAACCC 89 7796 7815 6-8-6 419 599398 2562 2581 Exon18 GAAACCCCTTATAGAAAACC 90 7797 7816 6-8-6 420 599399 2563 2582 Exon18 GGAAACCCCTTATAGAAAAC 91 7798 7817 6-8-6 421 599400 2564 2583 Exon18 AGGAAACCCCTTATAGAAAA 88 7799 7818 6-8-6 422 599401 2565 2584 Exon18 CAGGAAACCCCTTATAGAAA 85 7800 7819 6-8-6 423 599402 2566 2585 Exon18 GCAGGAAACCCCTTATAGAA 77 7801 7820 6-8-6 424 599403 2567 2586 Exon18 AGCAGGAAACCCCTTATAGA 85 7802 7821 6-8-6 425 599404 2568 2587 Exon18 CAGCAGGAAACCCCTTATAG 90 7803 7822 6-8-6 426 599405 2569 2588 Exon18 CCAGCAGGAAACCCCTTATA 89 7804 7823 6-8-6 427 599406 2570 2589 Exon18 TCCAGCAGGAAACCCCTTAT 72 7805 7824 6-8-6 428 599407 2571 2590 Exon18 GTCCAGCAGGAAACCCCTTA 87 7806 7825 6-8-6 237 599408 2572 2591 Exon18 TGTCCAGCAGGAAACCCCTT 87 7807 7826 6-8-6 429 599409 2573 2592 Exon18 CTGTCCAGCAGGAAACCCCT 83 7808 7827 6-8-6 430 599410 2574 2593 Exon18 CCTGTCCAGCAGGAAACCCC 88 7809 7828 6-8-6 431 599411 2575 2594 Exon18 CCCTGTCCAGCAGGAAACCC 45 7810 7829 6-8-6 432 599412 2576 2595 Exon18 CCCCTGTCCAGCAGGAAACC 66 7811 7830 6-8-6 433 599413 2577 2596 Exon18 GCCCCTGTCCAGCAGGAAAC 92 7812 7831 6-8-6 238 599414 2578 2597 Exon18 CGCCCCTGTCCAGCAGGAAA 92 7813 7832 6-8-6 434 599415 2579 2598 Exon18 ACGCCCCTGTCCAGCAGGAA 87 7814 7833 6-8-6 435 599416 2580 2599 Exon18 CACGCCCCTGTCCAGCAGGA 91 7815 7834 6-8-6 436 599417 2581 2600 Exon18 CCACGCCCCTGTCCAGCAGG 84 7816 7835 6-8-6 437 599357 2582 2600 Exon18 CCACGCCCCTGTCCAGCAG 88 7817 7835 5-9-5 708 599418 2582 2601 Exon18 CCCACGCCCCTGTCCAGCAG 85 7817 7836 6-8-6 438 599358 2583 2601 Exon18 CCCACGCCCCTGTCCAGCA 86 7818 7836 5-9-5 709 599419 2583 2602 Exon18 TCCCACGCCCCTGTCCAGCA 91 7818 7837 6-8-6 833 599359 2584 2602 Exon18 TCCCACGCCCCTGTCCAGC 85 7819 7837 5-9-5 834 599420 2584 2603 Exon18 ATCCCACGCCCCTGTCCAGC 91 7819 7838 6-8-6 440 599360 2585 2603 Exon18 ATCCCACGCCCCTGTCCAG 89 7820 7838 5-9-5 711 599421 2585 2604 Exon18 AATCCCACGCCCCTGTCCAG 87 7820 7839 6-8-6 441 599361 2586 2604 Exon18 AATCCCACGCCCCTGTCCA 89 7821 7839 5-9-5 712 599422 2586 2605 Exon18 CAATCCCACGCCCCTGTCCA 90 7821 7840 6-8-6 442 599362 2587 2605 Exon18 CAATCCCACGCCCCTGTCC 94 7822 7840 5-9-5 713 599423 2587 2606 Exon18 TCAATCCCACGCCCCTGTCC 85 7822 7841 6-8-6 841 599363 2588 2606 Exon18 TCAATCCCACGCCCCTGTC 88 7823 7841 5-9-5 714 599424 2588 2607 Exon18 TTCAATCCCACGCCCCTGTC 88 7823 7842 6-8-6 444 599364 2589 2607 Exon18 TTCAATCCCACGCCCCTGT 88 7824 7842 5-9-5 715 599425 2589 2608 Exon18 ATTCAATCCCACGCCCCTGT 68 7824 7843 6-8-6 445 599365 2590 2608 Exon18 ATTCAATCCCACGCCCCTG 48 7825 7843 5-9-5 716 599426 2590 2609 Exon18 AATTCAATCCCACGCCCCTG 55 7825 7844 6-8-6 446 599366 2591 2609 Exon18 AATTCAATCCCACGCCCCT 28 7826 7844 5-9-5 717 599427 2591 2610 Exon18 TAATTCAATCCCACGCCCCT 13 7826 7845 6-8-6 849 599367 2592 2610 Exon18 TAATTCAATCCCACGCCCC 21 7827 7845 5-9-5 718 599428 2592 2611 Exon18 TTAATTCAATCCCACGCCCC 39 7827 7846 6-8-6 448 599368 2593 2611 Exon18 TTAATTCAATCCCACGCCC 20 7828 7846 5-9-5 719 599429 2593 2612 Exon18 TTTAATTCAATCCCACGCCC 18 7828 7847 6-8-6 449 599369 2594 2612 Exon18 TTTAATTCAATCCCACGCC 78 7829 7847 5-9-5 720 599430 2594 2613 Exon18 TTTTAATTCAATCCCACGCC 24 7829 7848 6-8-6 450 599370 2595 2613 Exon18 TTTTAATTCAATCCCACGC 25 7830 7848 5-9-5 721 599431 2595 2614 Exon18 GTTTTAATTCAATCCCACGC 30 7830 7849 6-8-6 451 599371 2596 2614 Exon18 GTTTTAATTCAATCCCACG 84 7831 7849 5-9-5 722 599432 2596 2615 Exon18 TGTTTTAATTCAATCCCACG 29 7831 7850 6-8-6 452 599372 2597 2615 Exon18 TGTTTTAATTCAATCCCAC 83 7832 7850 5-9-5 723 599373 2598 2616 Exon18 CTGTTTTAATTCAATCCCA 81 7833 7851 5-9-5 724 599374 2599 2617 Exon18 GCTGTTTTAATTCAATCCC 26 7834 7852 5-9-5 725 599375 2600 2618 Exon18 AGCTGTTTTAATTCAATCC 26 7835 7853 5-9-5 726 599376 2601 2619 Exon18 CAGCTGTTTTAATTCAATC 62 7836 7854 5-9-5 727 599377 2602 2620 Exon18 GCAGCTGTTTTAATTCAAT 21 7837 7855 5-9-5 728 599378 2603 2621 Exon18 CGCAGCTGTTTTAATTCAA 90 7838 7856 5-9-5 729 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 95 7839 7858 5-10-5 867 599379 2604 2622 Exon18 TCGCAGCTGTTTTAATTCA 88 7839 7857 5-9-5 730 599380 2605 2623 Exon18 GTCGCAGCTGTTTTAATTC 37 7840 7858 5-9-5 869 599381 2606 2624 Exon18 TGTCGCAGCTGTTTTAATT 33 7841 7859 5-9-5 732 599382 2607 2625 Exon18 TTGTCGCAGCTGTTTTAAT 81 7842 7860 5-9-5 733 599383 2608 2626 Exon18 GTTGTCGCAGCTGTTTTAA 54 7843 7861 5-9-5 734 599384 2609 2627 Exon18 TGTTGTCGCAGCTGTTTTA 85 7844 7862 5-9-5 873 599385 2610 2628 Exon18/ TTGTTGTCGCAGCTGTTTT 59 n/a n/a 5-9-5 736 Repeat 599386 2611 2629 Exon18/ TTTGTTGTCGCAGCTGTTT 81 n/a n/a 5-9-5 737 Repeat 599387 2612 2630 Exon18/ TTTTGTTGTCGCAGCTGTT 80 n/a n/a 5-9-5 738 Repeat 599388 2613 2631 Exon18/ TTTTTGTTGTCGCAGCTGT 84 n/a n/a 5-9-5 739 Repeat

Example 6: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells

[0451] Additional antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 1,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0452] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as deoxy, MOE and cEt oligonucleotides. The deoxy, MOE and cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an cEt sugar modification, or a deoxy modification. The Chemistry column describes the sugar modifications of each oligonucleotide. k indicates an cEt sugar modification; d indicates deoxyribose; and e indicates a MOE modification.

[0453] Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity.

TABLE-US-00019 TABLE18 InhibitionofCFBmRNAbydeoxy,MOEandcEtoligonucleotidestargetingSEQIDNO:1or SEQIDNO:2 SEQID SEQID SEQID SEQID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target % start stop ID NO site site region Sequence inhibition site site Motif NO: 599513 2551 2566 Exon18 AAACCCAAATCCTCAT 11 7786 7801 ekkeekkdddddddkk 557 599514 2553 2568 Exon18 GAAAACCCAAATCCTC 13 7788 7803 ekkeekkdddddddkk 801 599515 2555 2570 Exon18 TAGAAAACCCAAATCC 54 7790 7805 ekkeekkdddddddkk 559 599516 2559 2574 Exon18 CTTATAGAAAACCCAA 16 7794 7809 ekkeekkdddddddkk 561 599517 2560 2575 Exon18 CCTTATAGAAAACCCA 29 7795 7810 ekkeekkdddddddkk 562 599518 2561 2576 Exon18 CCCTTATAGAAAACCC 55 7796 7811 ekkeekkdddddddkk 563 599519 2562 2577 Exon18 CCCCTTATAGAAAACC 31 7797 7812 ekkeekkdddddddkk 564 599520 2563 2578 Exon18 ACCCCTTATAGAAAAC 14 7798 7813 ekkeekkdddddddkk 565 599521 2564 2579 Exon18 AACCCCTTATAGAAAA 9 7799 7814 ekkeekkdddddddkk 566 599522 2565 2580 Exon18 AAACCCCTTATAGAAA 8 7800 7815 ekkeekkdddddddkk 567 599523 2566 2581 Exon18 GAAACCCCTTATAGAA 6 7801 7816 ekkeekkdddddddkk 568 599524 2567 2582 Exon18 GGAAACCCCTTATAGA 14 7802 7817 ekkeekkdddddddkk 569 599525 2568 2583 Exon18 AGGAAACCCCTTATAG 6 7803 7818 ekkeekkdddddddkk 570 599526 2569 2584 Exon18 CAGGAAACCCCTTATA 16 7804 7819 ekkeekkdddddddkk 571 599527 2570 2585 Exon18 GCAGGAAACCCCTTAT 0 7805 7820 ekkeekkdddddddkk 572 599528 2571 2586 Exon18 AGCAGGAAACCCCTTA 6 7806 7821 ekkeekkdddddddkk 573 599529 2572 2587 Exon18 CAGCAGGAAACCCCTT 6 7807 7822 ekkeekkdddddddkk 574 599530 2574 2589 Exon18 TCCAGCAGGAAACCCC 29 7809 7824 ekkeekkdddddddkk 576 599531 2575 2590 Exon18 GTCCAGCAGGAAACCC 64 7810 7825 ekkeekkdddddddkk 577 599532 2576 2591 Exon18 TGTCCAGCAGGAAACC 43 7811 7826 ekkeekkdddddddkk 578 599533 2577 2592 Exon18 CTGTCCAGCAGGAAAC 25 7812 7827 ekkeekkdddddddkk 820 599534 2578 2593 Exon18 CCTGTCCAGCAGGAAA 12 7813 7828 ekkeekkdddddddkk 580 599535 2580 2595 Exon18 CCCCTGTCCAGCAGGA 16 7815 7830 ekkeekkdddddddkk 582 599536 2582 2597 Exon18 CGCCCCTGTCCAGCAG 27 7817 7832 ekkeekkdddddddkk 584 599537 2583 2598 Exon18 ACGCCCCTGTCCAGCA 35 7818 7833 ekkeekkdddddddkk 585 599538 2584 2599 Exon18 CACGCCCCTGTCCAGC 26 7819 7834 ekkeekkdddddddkk 586 599539 2585 2600 Exon18 CCACGCCCCTGTCCAG 33 7820 7835 ekkeekkdddddddkk 587 599540 2586 2601 Exon18 CCCACGCCCCTGTCCA 27 7821 7836 ekkeekkdddddddkk 588 599541 2587 2602 Exon18 TCCCACGCCCCTGTCC 52 7822 7837 ekkeekkdddddddkk 589 599542 2588 2603 Exon18 ATCCCACGCCCCTGTC 16 7823 7838 ekkeekkdddddddkk 590 599543 2589 2604 Exon18 AATCCCACGCCCCTGT 19 7824 7839 ekkeekkdddddddkk 591 599544 2590 2605 Exon18 CAATCCCACGCCCCTG 33 7825 7840 ekkeekkdddddddkk 831 599545 2591 2606 Exon18 TCAATCCCACGCCCCT 24 7826 7841 ekkeekkdddddddkk 593 599546 2592 2607 Exon18 TTCAATCCCACGCCCC 54 7827 7842 ekkeekkdddddddkk 594 599547 2593 2608 Exon18 ATTCAATCCCACGCCC 87 7828 7843 ekkeekkdddddddkk 595 599548 2594 2609 Exon18 AATTCAATCCCACGCC 79 7829 7844 ekkeekkdddddddkk 596 599549 2595 2610 Exon18 TAATTCAATCCCACGC 62 7830 7845 ekkeekkdddddddkk 597 599550 2596 2611 Exon18 TTAATTCAATCCCACG 52 7831 7846 ekkeekkdddddddkk 598 599551 2597 2612 Exon18 TTTAATTCAATCCCAC 27 7832 7847 ekkeekkdddddddkk 599 599577 2597 2613 Exon18 TTTTAATTCAATCCCAC 90 7832 7848 eeekkdddddddkkeee 662 599552 2598 2613 Exon18 TTTTAATTCAATCCCA 92 7833 7848 ekkeekkdddddddkk 600 599578 2598 2614 Exon18 GTTTTAATTCAATCCCA 88 7833 7849 eeekkdddddddkkeee 663 599553 2599 2614 Exon18 GTTTTAATTCAATCCC 91 7834 7849 ekkeekkdddddddkk 601 599579 2599 2615 Exon18 TGTTTTAATTCAATCCC 79 7834 7850 eeekkdddddddkkeee 664 599554 2600 2615 Exon18 TGTTTTAATTCAATCC 90 7835 7850 ekkeekkdddddddkk 602 599580 2600 2616 Exon18 CTGTTTTAATTCAATCC 79 7835 7851 eeekkdddddddkkeee 665 599555 2601 2616 Exon18 CTGTTTTAATTCAATC 79 7836 7851 ekkeekkdddddddkk 846 599581 2601 2617 Exon18 GCTGTTTTAATTCAATC 90 7836 7852 eeekkdddddddkkeee 666 599556 2602 2617 Exon18 GCTGTTTTAATTCAAT 47 7837 7852 ekkeekkdddddddkk 604 599582 2602 2618 Exon18 AGCTGTTTTAATTCAAT 89 7837 7853 eeekkdddddddkkeee 849 599557 2603 2618 Exon18 AGCTGTTTTAATTCAA 67 7838 7853 ekkeekkdddddddkk 850 599583 2603 2619 Exon18 CAGCTGTTTTAATTCAA 49 7838 7854 eeekkdddddddkkeee 668 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 78 7839 7858 eeeeeddddddddddeee 317 ee 599558 2604 2619 Exon18 CAGCTGTTTTAATTCA 80 7839 7854 ekkeekkdddddddkk 606 599584 2604 2620 Exon18 GCAGCTGTTTTAATTCA 66 7839 7855 eeekkdddddddkkeee 669 599559 2605 2620 Exon18 GCAGCTGTTTTAATTC 38 7840 7855 ekkeekkdddddddkk 607 599585 2605 2621 Exon18 CGCAGCTGTTTTAATTC 80 7840 7856 eeekkdddddddkkeee 670 599560 2606 2621 Exon18 CGCAGCTGTTTTAATT 16 7841 7856 ekkeekkdddddddkk 608 599586 2606 2622 Exon18 TCGCAGCTGTTTTAATT 78 7841 7857 eeekkdddddddkkeee 671 599561 2607 2622 Exon18 TCGCAGCTGTTTTAAT 58 7842 7857 ekkeekkdddddddkk 609 599587 2607 2623 Exon18 GTCGCAGCTGTTTTAAT 81 7842 7858 eeekkdddddddkkeee 672 588860 2608 2623 Exon18 GTCGCAGCTGTTTTAA 92 7843 7858 eekddddddddddkke 610 599562 2608 2623 Exon18 GTCGCAGCTGTTTTAA 78 7843 7858 ekkeekkdddddddkk 610 599588 2608 2624 Exon18 TGTCGCAGCTGTTTTAA 81 7843 7859 eeekkdddddddkkeee 673 599563 2609 2624 Exon18 TGTCGCAGCTGTTTTA 86 7844 7859 ekkeekkdddddddkk 611 599589 2609 2625 Exon18 TTGTCGCAGCTGTTTTA 75 7844 7860 eeekkdddddddkkeee 674 599564 2610 2625 Exon18 TTGTCGCAGCTGTTTT 75 7845 7860 ekkeekkdddddddkk 612 599590 2610 2626 Exon18 GTTGTCGCAGCTGTTTT 88 7845 7861 eeekkdddddddkkeee 675 599565 2611 2626 Exon18 GTTGTCGCAGCTGTTT 65 7846 7861 ekkeekkdddddddkk 613 599591 2611 2627 Exon18 TGTTGTCGCAGCTGTTT 94 7846 7862 eeekkdddddddkkeee 676 599566 2612 2627 Exon18 TGTTGTCGCAGCTGTT 72 7847 7862 ekkeekkdddddddkk 614 599592 2612 2628 Exon18/ TTGTTGTCGCAGCTGTT 90 n/a n/a eeekkdddddddkkeee 677 Repeat 599567 2613 2628 Exon18/ TTGTTGTCGCAGCTGT 82 n/a n/a ekkeekkdddddddkk 615 Repeat 599593 2613 2629 Exon18/ TTTGTTGTCGCAGCTGT 95 n/a n/a eeekkdddddddkkeee 678 Repeat 599568 2614 2629 Exon18/ TTTGTTGTCGCAGCTG 92 n/a n/a ekkeekkdddddddkk 616 Repeat 599594 2614 2630 Exon18/ TTTTGTTGTCGCAGCTG 86 n/a n/a eeekkdddddddkkeee 679 Repeat 599569 2615 2630 Exon18/ TTTTGTTGTCGCAGCT 89 n/a n/a ekkeekkdddddddkk 617 Repeat 599595 2615 2631 Exon18/ TTTTTGTTGTCGCAGCT 76 n/a n/a eeekkdddddddkkeee 680 Repeat 599570 2616 2631 Exon18/ TTTTTGTTGTCGCAGC 95 n/a n/a ekkeekkdddddddkk 618 Repeat

Example 7: Antisense Inhibition of Human Complement Factor B (CFB) in HepG2 Cells

[0454] Additional antisense oligonucleotides were designed targeting human Complement Factor B (CFB) nucleic acid and were tested for their effects on CFB mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured HepG2 cells at a density of 20,000 cells per well were transfected using electroporation with 500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0455] The newly designed chimeric antisense oligonucleotides in the Tables below were designed as deoxy, MOE and cEt oligonucleotides, or as 5-8-5 MOE, 5-9-5 MOE, 5-10-5 MOE, 6-7-6-MOE, 3-10-5 MOE, or 6-8-6 MOE gapmers.

[0456] The deoxy, MOE and cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an cEt sugar modification, or a deoxy modification. The Chemistry column describes the sugar modifications of each oligonucleotide. k indicates an cEt sugar modification; d indicates deoxyribose; and e indicates a MOE modification.

[0457] The 5-8-5 MOE gapmers are 18 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 5-9-5 MOE gapmers are 19 nucleosides in length, wherein the central gap segment comprises of nine 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 5-10-5 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising five nucleosides each. The 3-10-5 MOE gapmers are 18 nucleosides in length, wherein the central gap segment comprises of ten 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising three and five nucleosides respectively. The 6-7-6 MOE gapmers are 19 nucleosides in length, wherein the central gap segment comprises of seven 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising six nucleosides each. The 6-8-6 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of eight 2-deoxynucleosides and is flanked by wing segments on the 5 direction and the 3 direction comprising six nucleosides each. Each nucleoside in the 5 wing segment and each nucleoside in the 3 wing segment has a 2-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

[0458] Start site indicates the 5-most nucleoside to which the gapmer is targeted in the human gene sequence. Stop site indicates the 3-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human CFB mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001710.5) or the human CFB genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007592.15 truncated from nucleotides 31852000 to 31861000), or both. n/a indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity.

TABLE-US-00020 TABLE19 InhibitionofCFBmRNAbydeoxy,MOEandcEtoligonucleotidestargetingSEQIDNO:1or SEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 601152 2551 2566 Exon18 AAACCCAAATCCTCAT 22 7786 7801 eekkddddddddkkee 557 601218 2551 2566 Exon18 AAACCCAAATCCTCAT 21 7786 7801 ekkkddddddddkeee 557 601153 2552 2567 Exon18 AAAACCCAAATCCTCA 27 7787 7802 eekkddddddddkkee 800 601219 2552 2567 Exon18 AAAACCCAAATCCTCA 19 7787 7802 ekkkddddddddkeee 800 601154 2553 2568 Exon18 GAAAACCCAAATCCTC 23 7788 7803 eekkddddddddkkee 558 601220 2553 2568 Exon18 GAAAACCCAAATCCTC 24 7788 7803 ekkkddddddddkeee 558 601155 2554 2569 Exon18 AGAAAACCCAAATCCT 20 7789 7804 eekkddddddddkkee 801 601221 2554 2569 Exon18 AGAAAACCCAAATCCT 0 7789 7804 ekkkddddddddkeee 801 601156 2555 2570 Exon18 TAGAAAACCCAAATCC 11 7790 7805 eekkddddddddkkee 559 601222 2555 2570 Exon18 TAGAAAACCCAAATCC 23 7790 7805 ekkkddddddddkeee 559 601157 2556 2571 Exon18 ATAGAAAACCCAAATC 9 7791 7806 eekkddddddddkkee 560 601223 2556 2571 Exon18 ATAGAAAACCCAAATC 0 7791 7806 ekkkddddddddkeee 560 601158 2557 2572 Exon18 TATAGAAAACCCAAAT 0 7792 7807 eekkddddddddkkee 802 601224 2557 2572 Exon18 TATAGAAAACCCAAAT 0 7792 7807 ekkkddddddddkeee 802 601159 2558 2573 Exon18 TTATAGAAAACCCAAA 2 7793 7808 eekkddddddddkkee 803 601225 2558 2573 Exon18 TTATAGAAAACCCAAA 0 7793 7808 ekkkddddddddkeee 803 601160 2559 2574 Exon18 CTTATAGAAAACCCAA 0 7794 7809 eekkddddddddkkee 561 601226 2559 2574 Exon18 CTTATAGAAAACCCAA 0 7794 7809 ekkkddddddddkeee 561 601161 2560 2575 Exon18 CCTTATAGAAAACCCA 1 7795 7810 eekkddddddddkkee 562 601227 2560 2575 Exon18 CCTTATAGAAAACCCA 14 7795 7810 ekkkddddddddkeee 562 601162 2561 2576 Exon18 CCCTTATAGAAAACCC 9 7796 7811 eekkddddddddkkee 563 601228 2561 2576 Exon18 CCCTTATAGAAAACCC 9 7796 7811 ekkkddddddddkeee 563 601163 2562 2577 Exon18 CCCCTTATAGAAAACC 0 7797 7812 eekkddddddddkkee 564 601164 2563 2578 Exon18 ACCCCTTATAGAAAAC 3 7798 7813 eekkddddddddkkee 565 601165 2564 2579 Exon18 AACCCCTTATAGAAAA 0 7799 7814 eekkddddddddkkee 566 601166 2565 2580 Exon18 AAACCCCTTATAGAAA 0 7800 7815 eekkddddddddkkee 567 601167 2566 2581 Exon18 GAAACCCCTTATAGAA 0 7801 7816 eekkddddddddkkee 568 601168 2567 2582 Exon18 GGAAACCCCTTATAGA 0 7802 7817 eekkddddddddkkee 569 601169 2568 2583 Exon18 AGGAAACCCCTTATAG 0 7803 7818 eekkddddddddkkee 570 601170 2569 2584 Exon18 CAGGAAACCCCTTATA 10 7804 7819 eekkddddddddkkee 571 601171 2570 2585 Exon18 GCAGGAAACCCCTTAT 9 7805 7820 eekkddddddddkkee 572 601172 2571 2586 Exon18 AGCAGGAAACCCCTTA 15 7806 7821 eekkddddddddkkee 573 601173 2572 2587 Exon18 CAGCAGGAAACCCCTT 29 7807 7822 eekkddddddddkkee 574 601174 2573 2588 Exon18 CCAGCAGGAAACCCCT 25 7808 7823 eekkddddddddkkee 575 601175 2574 2589 Exon18 TCCAGCAGGAAACCCC 15 7809 7824 eekkddddddddkkee 576 601176 2575 2590 Exon18 GTCCAGCAGGAAACCC 18 7810 7825 eekkddddddddkkee 577 601177 2576 2591 Exon18 TGTCCAGCAGGAAACC 10 7811 7826 eekkddddddddkkee 578 601178 2577 2592 Exon18 CTGTCCAGCAGGAAAC 11 7812 7827 eekkddddddddkkee 579 601179 2578 2593 Exon18 CCTGTCCAGCAGGAAA 19 7813 7828 eekkddddddddkkee 580 601180 2579 2594 Exon18 CCCTGTCCAGCAGGAA 7 7814 7829 eekkddddddddkkee 581 601181 2580 2595 Exon18 CCCCTGTCCAGCAGGA 3 7815 7830 eekkddddddddkkee 582 601182 2581 2596 Exon18 GCCCCTGTCCAGCAGG 0 7816 7831 eekkddddddddkkee 583 601183 2582 2597 Exon18 CGCCCCTGTCCAGCAG 4 7817 7832 eekkddddddddkkee 584 601184 2583 2598 Exon18 ACGCCCCTGTCCAGCA 14 7818 7833 eekkddddddddkkee 585 601185 2584 2599 Exon18 CACGCCCCTGTCCAGC 26 7819 7834 eekkddddddddkkee 586 601186 2585 2600 Exon18 CCACGCCCCTGTCCAG 8 7820 7835 eekkddddddddkkee 587 601187 2586 2601 Exon18 CCCACGCCCCTGTCCA 18 7821 7836 eekkddddddddkkee 588 601188 2587 2602 Exon18 TCCCACGCCCCTGTCC 20 7822 7837 eekkddddddddkkee 589 601189 2588 2603 Exon18 ATCCCACGCCCCTGTC 12 7823 7838 eekkddddddddkkee 590 601190 2589 2604 Exon18 AATCCCACGCCCCTGT 33 7824 7839 eekkddddddddkkee 591 601191 2590 2605 Exon18 CAATCCCACGCCCCTG 52 7825 7840 eekkddddddddkkee 592 601192 2591 2606 Exon18 TCAATCCCACGCCCCT 46 7826 7841 eekkddddddddkkee 593 601193 2592 2607 Exon18 TTCAATCCCACGCCCC 30 7827 7842 eekkddddddddkkee 594 601194 2593 2608 Exon18 ATTCAATCCCACGCCC 41 7828 7843 eekkddddddddkkee 595 601195 2594 2609 Exon18 AATTCAATCCCACGCC 40 7829 7844 eekkddddddddkkee 596 601196 2595 2610 Exon18 TAATTCAATCCCACGC 71 7830 7845 eekkddddddddkkee 597 601197 2596 2611 Exon18 TTAATTCAATCCCACG 42 7831 7846 eekkddddddddkkee 598 601198 2597 2612 Exon18 TTTAATTCAATCCCAC 63 7832 7847 eekkddddddddkkee 599 601199 2598 2613 Exon18 TTTTAATTCAATCCCA 51 7833 7848 eekkddddddddkkee 600 601200 2599 2614 Exon18 GTTTTAATTCAATCCC 65 7834 7849 eekkddddddddkkee 601 601201 2600 2615 Exon18 TGTTTTAATTCAATCC 49 7835 7850 eekkddddddddkkee 602 601202 2601 2616 Exon18 CTGTTTTAATTCAATC 33 7836 7851 eekkddddddddkkee 603 601203 2602 2617 Exon18 GCTGTTTTAATTCAAT 63 7837 7852 eekkddddddddkkee 604 601204 2603 2618 Exon18 AGCTGTTTTAATTCAA 69 7838 7853 eekkddddddddkkee 605 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATT 73 7839 7858 eeeeeddddddddddeeee 317 CA e 601205 2604 2619 Exon18 CAGCTGTTTTAATTCA 51 7839 7854 eekkddddddddkkee 606 601206 2605 2620 Exon18 GCAGCTGTTTTAATTC 43 7840 7855 eekkddddddddkkee 607 601207 2606 2621 Exon18 CGCAGCTGTTTTAATT 52 7841 7856 eekkddddddddkkee 608 601208 2607 2622 Exon18 TCGCAGCTGTTTTAAT 61 7842 7857 eekkddddddddkkee 609 588860 2608 2623 Exon18 GTCGCAGCTGTTTTAA 75 7843 7858 eekddddddddddkke 610 601209 2608 2623 Exon18 GTCGCAGCTGTTTTAA 73 7843 7858 eekkddddddddkkee 610 601210 2609 2624 Exon18 TGTCGCAGCTGTTTTA 80 7844 7859 eekkddddddddkkee 611 601211 2610 2625 Exon18 TTGTCGCAGCTGTTTT 64 7845 7860 eekkddddddddkkee 612 601212 2611 2626 Exon18 GTTGTCGCAGCTGTTT 86 7846 7861 eekkddddddddkkee 613 601213 2612 2627 Exon18 TGTTGTCGCAGCTGTT 87 7847 7862 eekkddddddddkkee 614 601214 2613 2628 Exon18/ TTGTTGTCGCAGCTGT 84 n/a n/a eekkddddddddkkee 615 Repeat 601215 2614 2629 Exon18/ TTTGTTGTCGCAGCTG 78 n/a n/a eekkddddddddkkee 616 Repeat 601216 2615 2630 Exon18/ TTTTGTTGTCGCAGCT 73 n/a n/a eekkddddddddkkee 617 Repeat 601217 2616 2631 Exon18/ TTTTTGTTGTCGCAGC 66 n/a n/a eekkddddddddkkee 618 Repeat

TABLE-US-00021 TABLE20 InhibitionofCFBmRNAbydeoxy,MOEandcEtoligonucleotidestargetingSEQIDNO:1or SEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 601284 2551 2566 Exon18 AAACCCAAATCCTCAT 8 7786 7801 ekkddddddddkkeee 557 601285 2552 2567 Exon18 AAAACCCAAATCCTCA 15 7787 7802 ekkddddddddkkeee 800 601286 2553 2568 Exon18 GAAAACCCAAATCCTC 21 7788 7803 ekkddddddddkkeee 558 601287 2554 2569 Exon18 AGAAAACCCAAATCCT 9 7789 7804 ekkddddddddkkeee 801 601288 2555 2570 Exon18 TAGAAAACCCAAATCC 0 7790 7805 ekkddddddddkkeee 559 601289 2556 2571 Exon18 ATAGAAAACCCAAATC 40 7791 7806 ekkddddddddkkeee 560 601290 2557 2572 Exon18 TATAGAAAACCCAAAT 16 7792 7807 ekkddddddddkkeee 802 601291 2558 2573 Exon18 TTATAGAAAACCCAAA 15 7793 7808 ekkddddddddkkeee 803 601292 2559 2574 Exon18 CTTATAGAAAACCCAA 5 7794 7809 ekkddddddddkkeee 561 601293 2560 2575 Exon18 CCTTATAGAAAACCCA 15 7795 7810 ekkddddddddkkeee 562 601294 2561 2576 Exon18 CCCTTATAGAAAACCC 3 7796 7811 ekkddddddddkkeee 563 601229 2562 2577 Exon18 CCCCTTATAGAAAACC 15 7797 7812 ekkkddddddddkeee 564 601295 2562 2577 Exon18 CCCCTTATAGAAAACC 5 7797 7812 ekkddddddddkkeee 564 601230 2563 2578 Exon18 ACCCCTTATAGAAAAC 14 7798 7813 ekkkddddddddkeee 565 601296 2563 2578 Exon18 ACCCCTTATAGAAAAC 0 7798 7813 ekkddddddddkkeee 565 601231 2564 2579 Exon18 AACCCCTTATAGAAAA 14 7799 7814 ekkkddddddddkeee 566 601297 2564 2579 Exon18 AACCCCTTATAGAAAA 14 7799 7814 ekkddddddddkkeee 566 601232 2565 2580 Exon18 AAACCCCTTATAGAAA 15 7800 7815 ekkkddddddddkeee 567 601298 2565 2580 Exon18 AAACCCCTTATAGAAA 7 7800 7815 ekkddddddddkkeee 567 601233 2566 2581 Exon18 GAAACCCCTTATAGAA 0 7801 7816 ekkkddddddddkeee 568 601299 2566 2581 Exon18 GAAACCCCTTATAGAA 0 7801 7816 ekkddddddddkkeee 568 601234 2567 2582 Exon18 GGAAACCCCTTATAGA 0 7802 7817 ekkkddddddddkeee 569 601300 2567 2582 Exon18 GGAAACCCCTTATAGA 9 7802 7817 ekkddddddddkkeee 569 601235 2568 2583 Exon18 AGGAAACCCCTTATAG 3 7803 7818 ekkkddddddddkeee 570 601301 2568 2583 Exon18 AGGAAACCCCTTATAG 14 7803 7818 ekkddddddddkkeee 570 601236 2569 2584 Exon18 CAGGAAACCCCTTATA 0 7804 7819 ekkkddddddddkeee 571 601302 2569 2584 Exon18 CAGGAAACCCCTTATA 0 7804 7819 ekkddddddddkkeee 571 601237 2570 2585 Exon18 GCAGGAAACCCCTTAT 16 7805 7820 ekkkddddddddkeee 572 601303 2570 2585 Exon18 GCAGGAAACCCCTTAT 16 7805 7820 ekkddddddddkkeee 572 601238 2571 2586 Exon18 AGCAGGAAACCCCTTA 11 7806 7821 ekkkddddddddkeee 573 601304 2571 2586 Exon18 AGCAGGAAACCCCTTA 10 7806 7821 ekkddddddddkkeee 573 601239 2572 2587 Exon18 CAGCAGGAAACCCCTT 21 7807 7822 ekkkddddddddkeee 574 601305 2572 2587 Exon18 CAGCAGGAAACCCCTT 7 7807 7822 ekkddddddddkkeee 574 601240 2573 2588 Exon18 CCAGCAGGAAACCCCT 6 7808 7823 ekkkddddddddkeee 575 601241 2574 2589 Exon18 TCCAGCAGGAAACCCC 10 7809 7824 ekkkddddddddkeee 576 601242 2575 2590 Exon18 GTCCAGCAGGAAACCC 19 7810 7825 ekkkddddddddkeee 577 601243 2576 2591 Exon18 TGTCCAGCAGGAAACC 10 7811 7826 ekkkddddddddkeee 578 601244 2577 2592 Exon18 CTGTCCAGCAGGAAAC 28 7812 7827 ekkkddddddddkeee 579 601245 2578 2593 Exon18 CCTGTCCAGCAGGAAA 5 7813 7828 ekkkddddddddkeee 580 601246 2579 2594 Exon18 CCCTGTCCAGCAGGAA 18 7814 7829 ekkkddddddddkeee 581 601247 2580 2595 Exon18 CCCCTGTCCAGCAGGA 4 7815 7830 ekkkddddddddkeee 582 601248 2581 2596 Exon18 GCCCCTGTCCAGCAGG 6 7816 7831 ekkkddddddddkeee 583 601249 2582 2597 Exon18 CGCCCCTGTCCAGCAG 18 7817 7832 ekkkddddddddkeee 584 601250 2583 2598 Exon18 ACGCCCCTGTCCAGCA 26 7818 7833 ekkkddddddddkeee 585 601251 2584 2599 Exon18 CACGCCCCTGTCCAGC 27 7819 7834 ekkkddddddddkeee 586 601252 2585 2600 Exon18 CCACGCCCCTGTCCAG 21 7820 7835 ekkkddddddddkeee 587 601253 2586 2601 Exon18 CCCACGCCCCTGTCCA 0 7821 7836 ekkkddddddddkeee 588 601254 2587 2602 Exon18 TCCCACGCCCCTGTCC 31 7822 7837 ekkkddddddddkeee 589 601255 2588 2603 Exon18 ATCCCACGCCCCTGTC 3 7823 7838 ekkkddddddddkeee 590 601256 2589 2604 Exon18 AATCCCACGCCCCTGT 21 7824 7839 ekkkddddddddkeee 591 601257 2590 2605 Exon18 CAATCCCACGCCCCTG 47 7825 7840 ekkkddddddddkeee 592 601258 2591 2606 Exon18 TCAATCCCACGCCCCT 48 7826 7841 ekkkddddddddkeee 593 601259 2592 2607 Exon18 TTCAATCCCACGCCCC 38 7827 7842 ekkkddddddddkeee 594 601260 2593 2608 Exon18 ATTCAATCCCACGCCC 33 7828 7843 ekkkddddddddkeee 595 601261 2594 2609 Exon18 AATTCAATCCCACGCC 17 7829 7844 ekkkddddddddkeee 596 601262 2595 2610 Exon18 TAATTCAATCCCACGC 40 7830 7845 ekkkddddddddkeee 597 601263 2596 2611 Exon18 TTAATTCAATCCCACG 31 7831 7846 ekkkddddddddkeee 598 601264 2597 2612 Exon18 TTTAATTCAATCCCAC 72 7832 7847 ekkkddddddddkeee 599 601265 2598 2613 Exon18 TTTTAATTCAATCCCA 48 7833 7848 ekkkddddddddkeee 600 601266 2599 2614 Exon18 GTTTTAATTCAATCCC 64 7834 7849 ekkkddddddddkeee 601 601267 2600 2615 Exon18 TGTTTTAATTCAATCC 43 7835 7850 ekkkddddddddkeee 602 601268 2601 2616 Exon18 CTGTTTTAATTCAATC 44 7836 7851 ekkkddddddddkeee 603 601269 2602 2617 Exon18 GCTGTTTTAATTCAAT 66 7837 7852 ekkkddddddddkeee 604 601270 2603 2618 Exon18 AGCTGTTTTAATTCAA 47 7838 7853 ekkkddddddddkeee 605 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATT 3 7839 7858 eeeeeddddddddddeeee 317 CA e 601271 2604 2619 Exon18 CAGCTGTTTTAATTCA 26 7839 7854 ekkkddddddddkeee 606 601272 2605 2620 Exon18 GCAGCTGTTTTAATTC 33 7840 7855 ekkkddddddddkeee 607 601273 2606 2621 Exon18 CGCAGCTGTTTTAATT 34 7841 7856 ekkkddddddddkeee 608 601274 2607 2622 Exon18 TCGCAGCTGTTTTAAT 39 7842 7857 ekkkddddddddkeee 609 588860 2608 2623 Exon18 GTCGCAGCTGTTTTAA 72 7843 7858 eekddddddddddkke 610 601275 2608 2623 Exon18 GTCGCAGCTGTTTTAA 65 7843 7858 ekkkddddddddkeee 610 601276 2609 2624 Exon18 TGTCGCAGCTGTTTTA 65 7844 7859 ekkkddddddddkeee 611 601277 2610 2625 Exon18 TTGTCGCAGCTGTTTT 51 7845 7860 ekkkddddddddkeee 612 601278 2611 2626 Exon18 GTTGTCGCAGCTGTTT 78 7846 7861 ekkkddddddddkeee 613 601279 2612 2627 Exon18 TGTTGTCGCAGCTGTT 79 7847 7862 ekkkddddddddkeee 614 601280 2613 2628 Exon18/ TTGTTGTCGCAGCTGT 70 n/a n/a ekkkddddddddkeee 615 Repeat 601281 2614 2629 Exon18/ TTTGTTGTCGCAGCTG 78 n/a n/a ekkkddddddddkeee 616 Repeat 601282 2615 2630 Exon18/ TTTTGTTGTCGCAGCT 68 n/a n/a ekkkddddddddkeee 617 Repeat 601283 2616 2631 Exon18/ TTTTTGTTGTCGCAGC 61 n/a n/a ekkkddddddddkeee 618 Repeat

TABLE-US-00022 TABLE21 InhibitionofCFBmRNAbydeoxy,MOEandcEtoligonucleotidestaretingSEQIDNO:1or SEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target %in- start stop ID NO site site region Sequence hibition site site Motif NO: 601306 2573 2588 Exon18 CCAGCAGGAAACCCCT 22 7808 7823 ekkddddddddkkeee 575 601307 2574 2589 Exon18 TCCAGCAGGAAACCCC 22 7809 7824 ekkddddddddkkeee 576 601308 2575 2590 Exon18 GTCCAGCAGGAAACCC 33 7810 7825 ekkddddddddkkeee 577 601309 2576 2591 Exon18 TGTCCAGCAGGAAACC 33 7811 7826 ekkddddddddkkeee 578 601310 2577 2592 Exon18 CTGTCCAGCAGGAAAC 28 7812 7827 ekkddddddddkkeee 579 601311 2578 2593 Exon18 CCTGTCCAGCAGGAAA 33 7813 7828 ekkddddddddkkeee 580 601312 2579 2594 Exon18 CCCTGTCCAGCAGGAA 13 7814 7829 ekkddddddddkkeee 581 601313 2580 2595 Exon18 CCCCTGTCCAGCAGGA 32 7815 7830 ekkddddddddkkeee 582 601314 2581 2596 Exon18 GCCCCTGTCCAGCAGG 0 7816 7831 ekkddddddddkkeee 583 601315 2582 2597 Exon18 CGCCCCTGTCCAGCAG 36 7817 7832 ekkddddddddkkeee 584 601316 2583 2598 Exon18 ACGCCCCTGTCCAGCA 39 7818 7833 ekkddddddddkkeee 585 601317 2584 2599 Exon18 CACGCCCCTGTCCAGC 33 7819 7834 ekkddddddddkkeee 586 601356 2584 2599 Exon18 CACGCCCCTGTCCAGC 27 7819 7834 kkkddddddddkeeee 586 601318 2585 2600 Exon18 CCACGCCCCTGTCCAG 35 7820 7835 ekkddddddddkkeee 587 601357 2585 2600 Exon18 CCACGCCCCTGTCCAG 26 7820 7835 kkkddddddddkeeee 587 601319 2586 2601 Exon18 CCCACGCCCCTGTCCA 33 7821 7836 ekkddddddddkkeee 588 601358 2586 2601 Exon18 CCCACGCCCCTGTCCA 26 7821 7836 kkkddddddddkeeee 588 601320 2587 2602 Exon18 TCCCACGCCCCTGTCC 25 7822 7837 ekkddddddddkkeee 589 601359 2587 2602 Exon18 TCCCACGCCCCTGTCC 23 7822 7837 kkkddddddddkeeee 589 601321 2588 2603 Exon18 ATCCCACGCCCCTGTC 50 7823 7838 ekkddddddddkkeee 590 601360 2588 2603 Exon18 ATCCCACGCCCCTGTC 33 7823 7838 kkkddddddddkeeee 590 601322 2589 2604 Exon18 AATCCCACGCCCCTGT 52 7824 7839 ekkddddddddkkeee 591 601361 2589 2604 Exon18 AATCCCACGCCCCTGT 48 7824 7839 kkkddddddddkeeee 591 601323 2590 2605 Exon18 CAATCCCACGCCCCTG 67 7825 7840 ekkddddddddkkeee 592 601362 2590 2605 Exon18 CAATCCCACGCCCCTG 51 7825 7840 kkkddddddddkeeee 592 601324 2591 2606 Exon18 TCAATCCCACGCCCCT 42 7826 7841 ekkddddddddkkeee 593 601363 2591 2606 Exon18 TCAATCCCACGCCCCT 42 7826 7841 kkkddddddddkeeee 593 601325 2592 2607 Exon18 TTCAATCCCACGCCCC 52 7827 7842 ekkddddddddkkeee 594 601364 2592 2607 Exon18 TTCAATCCCACGCCCC 48 7827 7842 kkkddddddddkeeee 594 601326 2593 2608 Exon18 ATTCAATCCCACGCCC 27 7828 7843 ekkddddddddkkeee 595 601365 2593 2608 Exon18 ATTCAATCCCACGCCC 36 7828 7843 kkkddddddddkeeee 595 601327 2594 2609 Exon18 AATTCAATCCCACGCC 66 7829 7844 ekkddddddddkkeee 596 601366 2594 2609 Exon18 AATTCAATCCCACGCC 49 7829 7844 kkkddddddddkeeee 596 601328 2595 2610 Exon18 TAATTCAATCCCACGC 55 7830 7845 ekkddddddddkkeee 597 601367 2595 2610 Exon18 TAATTCAATCCCACGC 57 7830 7845 kkkddddddddkeeee 597 601329 2596 2611 Exon18 TTAATTCAATCCCACG 69 7831 7846 ekkddddddddkkeee 598 601368 2596 2611 Exon18 TTAATTCAATCCCACG 68 7831 7846 kkkddddddddkeeee 598 601330 2597 2612 Exon18 TTTAATTCAATCCCAC 58 7832 7847 ekkddddddddkkeee 599 601369 2597 2612 Exon18 TTTAATTCAATCCCAC 65 7832 7847 kkkddddddddkeeee 599 601331 2598 2613 Exon18 TTTTAATTCAATCCCA 45 7833 7848 ekkddddddddkkeee 600 601370 2598 2613 Exon18 TTTTAATTCAATCCCA 42 7833 7848 kkkddddddddkeeee 600 601332 2599 2614 Exon18 GTTTTAATTCAATCCC 84 7834 7849 ekkddddddddkkeee 601 601371 2599 2614 Exon18 GTTTTAATTCAATCCC 79 7834 7849 kkkddddddddkeeee 601 601333 2600 2615 Exon18 TGTTTTAATTCAATCC 61 7835 7850 ekkddddddddkkeee 602 601372 2600 2615 Exon18 TGTTTTAATTCAATCC 71 7835 7850 kkkddddddddkeeee 602 601334 2601 2616 Exon18 CTGTTTTAATTCAATC 61 7836 7851 ekkddddddddkkeee 603 601373 2601 2616 Exon18 CTGTTTTAATTCAATC 57 7836 7851 kkkddddddddkeeee 603 601335 2602 2617 Exon18 GCTGTTTTAATTCAAT 73 7837 7852 ekkddddddddkkeee 604 601374 2602 2617 Exon18 GCTGTTTTAATTCAAT 66 7837 7852 kkkddddddddkeeee 604 601336 2603 2618 Exon18 AGCTGTTTTAATTCAA 64 7838 7853 ekkddddddddkkeee 605 601375 2603 2618 Exon18 AGCTGTTTTAATTCAA 61 7838 7853 kkkddddddddkeeee 605 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATT 66 7839 7858 eeeeedddddddddde 317 CA eeee 601337 2604 2619 Exon18 CAGCTGTTTTAATTCA 53 7839 7854 ekkddddddddkkeee 606 601376 2604 2619 Exon18 CAGCTGTTTTAATTCA 39 7839 7854 kkkddddddddkeeee 606 601338 2605 2620 Exon18 GCAGCTGTTTTAATTC 67 7840 7855 ekkddddddddkkeee 607 601377 2605 2620 Exon18 GCAGCTGTTTTAATTC 67 7840 7855 kkkddddddddkeeee 607 601339 2606 2621 Exon18 CGCAGCTGTTTTAATT 63 7841 7856 ekkddddddddkkeee 608 601378 2606 2621 Exon18 CGCAGCTGTTTTAATT 60 7841 7856 kkkddddddddkeeee 608 601340 2607 2622 Exon18 TCGCAGCTGTTTTAAT 40 7842 7857 ekkddddddddkkeee 609 601379 2607 2622 Exon18 TCGCAGCTGTTTTAAT 36 7842 7857 kkkddddddddkeeee 609 588860 2608 2623 Exon18 GTCGCAGCTGTTTTAA 84 7843 7858 eekddddddddddkke 610 601341 2608 2623 Exon18 GTCGCAGCTGTTTTAA 74 7843 7858 ekkddddddddkkeee 610 601380 2608 2623 Exon18 GTCGCAGCTGTTTTAA 78 7843 7858 kkkddddddddkeeee 610 601342 2609 2624 Exon18 TGTCGCAGCTGTTTTA 68 7844 7859 ekkddddddddkkeee 611 601381 2609 2624 Exon18 TGTCGCAGCTGTTTTA 66 7844 7859 kkkddddddddkeeee 611 601343 2610 2625 Exon18 TTGTCGCAGCTGTTTT 71 7845 7860 ekkddddddddkkeee 612 601382 2610 2625 Exon18 TTGTCGCAGCTGTTTT 84 7845 7860 kkkddddddddkeeee 612 601344 2611 2626 Exon18 GTTGTCGCAGCTGTTT 87 7846 7861 ekkddddddddkkeee 613 601383 2611 2626 Exon18 GTTGTCGCAGCTGTTT 85 7846 7861 kkkddddddddkeeee 613 601345 2612 2627 Exon18 TGTTGTCGCAGCTGTT 82 7847 7862 ekkddddddddkkeee 614 601384 2612 2627 Exon18 TGTTGTCGCAGCTGTT 79 7847 7862 kkkddddddddkeeee 614 601346 2613 2628 Exon18/ TTGTTGTCGCAGCTGT 73 n/a n/a ekkddddddddkkeee 615 Repeat 601385 2613 2628 Exon18/ TTGTTGTCGCAGCTGT 84 n/a n/a kkkddddddddkeeee 615 Repeat 601347 2614 2629 Exon18/ TTTGTTGTCGCAGCTG 70 n/a n/a ekkddddddddkkeee 616 Repeat 601386 2614 2629 Exon18/ TTTGTTGTCGCAGCTG 71 n/a n/a kkkddddddddkeeee 616 Repeat 601348 2615 2630 Exon18/ TTTTGTTGTCGCAGCT 71 n/a n/a ekkddddddddkkeee 617 Repeat 601387 2615 2630 Exon18/ TTTTGTTGTCGCAGCT 76 n/a n/a kkkddddddddkeeee 617 Repeat 601349 2616 2631 Exon18/ TTTTTGTTGTCGCAGC 71 n/a n/a ekkddddddddkkeee 618 Repeat 601388 2616 2631 Exon18/ TTTTTGTTGTCGCAGC 67 n/a n/a kkkddddddddkeeee 618 Repeat

TABLE-US-00023 TABLE22 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 NO:2 NO:2 SEQ ISIS start stop Target % start stop ID NO site site region Sequence inhibition site site Motif NO: 599357 2582 2600 Exon18 CCACGCCCCTGTCCAGCAG 26 7817 7835 5-9-5 708 599358 2583 2601 Exon18 CCCACGCCCCTGTCCAGCA 22 7818 7836 5-9-5 709 599359 2584 2602 Exon18 TCCCACGCCCCTGTCCAGC 13 7819 7837 5-9-5 710 599360 2585 2603 Exon18 ATCCCACGCCCCTGTCCAG 7 7820 7838 5-9-5 711 599361 2586 2604 Exon18 AATCCCACGCCCCTGTCCA 11 7821 7839 5-9-5 712 599362 2587 2605 Exon18 CAATCCCACGCCCCTGTCC 14 7822 7840 5-9-5 713 599363 2588 2606 Exon18 TCAATCCCACGCCCCTGTC 17 7823 7841 5-9-5 714 599364 2589 2607 Exon18 TTCAATCCCACGCCCCTGT 20 7824 7842 5-9-5 715 599365 2590 2608 Exon18 ATTCAATCCCACGCCCCTG 22 7825 7843 5-9-5 716 599366 2591 2609 Exon18 AATTCAATCCCACGCCCCT 13 7826 7844 5-9-5 717 599367 2592 2610 Exon18 TAATTCAATCCCACGCCCC 11 7827 7845 5-9-5 718 599368 2593 2611 Exon18 TTAATTCAATCCCACGCCC 10 7828 7846 5-9-5 719 599369 2594 2612 Exon18 TTTAATTCAATCCCACGCC 19 7829 7847 5-9-5 720 599370 2595 2613 Exon18 TTTTAATTCAATCCCACGC 23 7830 7848 5-9-5 721 599371 2596 2614 Exon18 GTTTTAATTCAATCCCACG 4 7831 7849 5-9-5 722 599372 2597 2615 Exon18 TGTTTTAATTCAATCCCAC 16 7832 7850 5-9-5 723 599373 2598 2616 Exon18 CTGTTTTAATTCAATCCCA 3 7833 7851 5-9-5 724 599374 2599 2617 Exon18 GCTGTTTTAATTCAATCCC 10 7834 7852 5-9-5 725 599375 2600 2618 Exon18 AGCTGTTTTAATTCAATCC 17 7835 7853 5-9-5 726 599376 2601 2619 Exon18 CAGCTGTTTTAATTCAATC 18 7836 7854 5-9-5 727 599377 2602 2620 Exon18 GCAGCTGTTTTAATTCAAT 22 7837 7855 5-9-5 728 599378 2603 2621 Exon18 CGCAGCTGTTTTAATTCAA 11 7838 7856 5-9-5 729 599511 2552 2571 Exon18 ATAGAAAACCCAAATCCTCA 7 7787 7806 6-8-6 410 599389 2553 2572 Exon18 TATAGAAAACCCAAATCCTC 22 7788 7807 6-8-6 411 599390 2554 2573 Exon18 TTATAGAAAACCCAAATCCT 21 7789 7808 6-8-6 412 599391 2555 2574 Exon18 CTTATAGAAAACCCAAATCC 27 7790 7809 6-8-6 413 599392 2556 2575 Exon18 CCTTATAGAAAACCCAAATC 30 7791 7810 6-8-6 414 599393 2557 2576 Exon18 CCCTTATAGAAAACCCAAAT 30 7792 7811 6-8-6 415 599394 2558 2577 Exon18 CCCCTTATAGAAAACCCAAA 28 7793 7812 6-8-6 416 599395 2559 2578 Exon18 ACCCCTTATAGAAAACCCAA 23 7794 7813 6-8-6 417 599396 2560 2579 Exon18 AACCCCTTATAGAAAACCCA 53 7795 7814 6-8-6 418 599397 2561 2580 Exon18 AAACCCCTTATAGAAAACCC 33 7796 7815 6-8-6 419 599398 2562 2581 Exon18 GAAACCCCTTATAGAAAACC 58 7797 7816 6-8-6 420 599399 2563 2582 Exon18 GGAAACCCCTTATAGAAAAC 23 7798 7817 6-8-6 421 599400 2564 2583 Exon18 AGGAAACCCCTTATAGAAAA 54 7799 7818 6-8-6 422 599401 2565 2584 Exon18 CAGGAAACCCCTTATAGAAA 30 7800 7819 6-8-6 423 599402 2566 2585 Exon18 GCAGGAAACCCCTTATAGAA 25 7801 7820 6-8-6 424 599403 2567 2586 Exon18 AGCAGGAAACCCCTTATAGA 17 7802 7821 6-8-6 425 599404 2568 2587 Exon18 CAGCAGGAAACCCCTTATAG 20 7803 7822 6-8-6 426 599405 2569 2588 Exon18 CCAGCAGGAAACCCCTTATA 12 7804 7823 6-8-6 427 599406 2570 2589 Exon18 TCCAGCAGGAAACCCCTTAT 51 7805 7824 6-8-6 428 599407 2571 2590 Exon18 GTCCAGCAGGAAACCCCTTA 39 7806 7825 6-8-6 237 599408 2572 2591 Exon18 TGTCCAGCAGGAAACCCCTT 53 7807 7826 6-8-6 429 599409 2573 2592 Exon18 CTGTCCAGCAGGAAACCCCT 65 7808 7827 6-8-6 430 599410 2574 2593 Exon18 CCTGTCCAGCAGGAAACCCC 56 7809 7828 6-8-6 431 599411 2575 2594 Exon18 CCCTGTCCAGCAGGAAACCC 60 7810 7829 6-8-6 432 599412 2576 2595 Exon18 CCCCTGTCCAGCAGGAAACC 61 7811 7830 6-8-6 433 599413 2577 2596 Exon18 GCCCCTGTCCAGCAGGAAAC 40 7812 7831 6-8-6 238 599414 2578 2597 Exon18 CGCCCCTGTCCAGCAGGAAA 41 7813 7832 6-8-6 434 599415 2579 2598 Exon18 ACGCCCCTGTCCAGCAGGAA 37 7814 7833 6-8-6 435 599416 2580 2599 Exon18 CACGCCCCTGTCCAGCAGGA 54 7815 7834 6-8-6 436 599417 2581 2600 Exon18 CCACGCCCCTGTCCAGCAGG 36 7816 7835 6-8-6 437 599418 2582 2601 Exon18 CCCACGCCCCTGTCCAGCAG 53 7817 7836 6-8-6 438 599419 2583 2602 Exon18 TCCCACGCCCCTGTCCAGCA 54 7818 7837 6-8-6 439 599420 2584 2603 Exon18 ATCCCACGCCCCTGTCCAGC 50 7819 7838 6-8-6 440 599421 2585 2604 Exon18 AATCCCACGCCCCTGTCCAG 48 7820 7839 6-8-6 441 599422 2586 2605 Exon18 CAATCCCACGCCCCTGTCCA 55 7821 7840 6-8-6 442 599423 2587 2606 Exon18 TCAATCCCACGCCCCTGTCC 75 7822 7841 6-8-6 443 599424 2588 2607 Exon18 TTCAATCCCACGCCCCTGTC 69 7823 7842 6-8-6 444 599425 2589 2608 Exon18 ATTCAATCCCACGCCCCTGT 77 7824 7843 6-8-6 445 599426 2590 2609 Exon18 AATTCAATCCCACGCCCCTG 60 7825 7844 6-8-6 446 599427 2591 2610 Exon18 TAATTCAATCCCACGCCCCT 72 7826 7845 6-8-6 447 599428 2592 2611 Exon18 TTAATTCAATCCCACGCCCC 81 7827 7846 6-8-6 448 599429 2593 2612 Exon18 TTTAATTCAATCCCACGCCC 68 7828 7847 6-8-6 449 599430 2594 2613 Exon18 TTTTAATTCAATCCCACGCC 58 7829 7848 6-8-6 450 599431 2595 2614 Exon18 GTTTTAATTCAATCCCACGC 70 7830 7849 6-8-6 451 599432 2596 2615 Exon18 TGTTTTAATTCAATCCCACG 85 7831 7850 6-8-6 452 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 85 7839 7858 5-10-5 317 599379 2604 2622 Exon18 TCGCAGCTGTTTTAATTCA 73 7839 7857 5-9-5 730 599380 2605 2623 Exon18 GTCGCAGCTGTTTTAATTC 77 7840 7858 5-9-5 731 599381 2606 2624 Exon18 TGTCGCAGCTGTTTTAATT 69 7841 7859 5-9-5 732 599382 2607 2625 Exon18 TTGTCGCAGCTGTTTTAAT 58 7842 7860 5-9-5 733 599383 2608 2626 Exon18 GTTGTCGCAGCTGTTTTAA 52 7843 7861 5-9-5 734 599384 2609 2627 Exon18 TGTTGTCGCAGCTGTTTTA 63 7844 7862 5-9-5 735 599385 2610 2628 Exon18/ TTGTTGTCGCAGCTGTTTT 53 n/a n/a 5-9-5 736 Repeat 599386 2611 2629 Exon18/ TTTGTTGTCGCAGCTGTTT 63 n/a n/a 5-9-5 737 Repeat 599387 2612 2630 Exon18/ TTTTGTTGTCGCAGCTGTT 64 n/a n/a 5-9-5 438 Repeat 599388 2613 2631 Exon18/ TTTTTGTTGTCGCAGCTGT 66 n/a n/a 5-9-5 739 Repeat

TABLE-US-00024 TABLE23 InhibitionofCFBmRNAbyMOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID IDNO: IDNO: NO:1 NO:1 % 2 2 SEQ ISIS start stop Target in- start stop ID NO site site region Sequence hibition site site Motif NO: 599213 2553 2570 Exon18 TAGAAAACCCAAATCCTC 0 7788 7805 3-10-5 785 599214 2554 2571 Exon18 ATAGAAAACCCAAATCCT 0 7789 7806 3-10-5 786 599215 2555 2572 Exon18 TATAGAAAACCCAAATCC 36 7790 7807 3-10-5 787 599216 2556 2573 Exon18 TTATAGAAAACCCAAATC 8 7791 7808 3-10-5 788 599217 2557 2574 Exon18 CTTATAGAAAACCCAAAT 5 7792 7809 3-10-5 789 599218 2558 2575 Exon18 CCTTATAGAAAACCCAAA 0 7793 7810 3-10-5 790 599219 2559 2576 Exon18 CCCTTATAGAAAACCCAA 8 7794 7811 3-10-5 791 599220 2560 2577 Exon18 CCCCTTATAGAAAACCCA 0 7795 7812 3-10-5 740 599221 2561 2578 Exon18 ACCCCTTATAGAAAACCC 54 7796 7813 3-10-5 741 599222 2562 2579 Exon18 AACCCCTTATAGAAAACC 3 7797 7814 3-10-5 742 599223 2563 2580 Exon18 AAACCCCTTATAGAAAAC 0 7798 7815 3-10-5 743 599224 2564 2581 Exon18 GAAACCCCTTATAGAAAA 0 7799 7816 3-10-5 744 599225 2566 2583 Exon18 AGGAAACCCCTTATAGAA 60 7801 7818 3-10-5 745 599226 2567 2584 Exon18 CAGGAAACCCCTTATAGA 0 7802 7819 3-10-5 746 599227 2568 2585 Exon18 GCAGGAAACCCCTTATAG 37 7803 7820 3-10-5 747 599228 2569 2586 Exon18 AGCAGGAAACCCCTTATA 0 7804 7821 3-10-5 748 599229 2570 2587 Exon18 CAGCAGGAAACCCCTTAT 39 7805 7822 3-10-5 749 599230 2571 2588 Exon18 CCAGCAGGAAACCCCTTA 10 7806 7823 3-10-5 750 599231 2572 2589 Exon18 TCCAGCAGGAAACCCCTT 16 7807 7824 3-10-5 751 599232 2573 2590 Exon18 GTCCAGCAGGAAACCCCT 9 7808 7825 3-10-5 752 599233 2574 2591 Exon18 TGTCCAGCAGGAAACCCC 44 7809 7826 3-10-5 753 599234 2575 2592 Exon18 CTGTCCAGCAGGAAACCC 14 7810 7827 3-10-5 754 599235 2576 2593 Exon18 CCTGTCCAGCAGGAAACC 0 7811 7828 3-10-5 755 599236 2577 2594 Exon18 CCCTGTCCAGCAGGAAAC 43 7812 7829 3-10-5 756 599237 2578 2595 Exon18 CCCCTGTCCAGCAGGAAA 0 7813 7830 3-10-5 757 599238 2580 2597 Exon18 CGCCCCTGTCCAGCAGGA 9 7815 7832 3-10-5 758 599239 2581 2598 Exon18 ACGCCCCTGTCCAGCAGG 36 7816 7833 3-10-5 759 599240 2582 2599 Exon18 CACGCCCCTGTCCAGCAG 11 7817 7834 3-10-5 760 599241 2583 2600 Exon18 CCACGCCCCTGTCCAGCA 51 7818 7835 3-10-5 761 599242 2584 2601 Exon18 CCCACGCCCCTGTCCAGC 7 7819 7836 3-10-5 762 599243 2585 2602 Exon18 TCCCACGCCCCTGTCCAG 47 7820 7837 3-10-5 763 599244 2586 2603 Exon18 ATCCCACGCCCCTGTCCA 37 7821 7838 3-10-5 764 599245 2587 2604 Exon18 AATCCCACGCCCCTGTCC 35 7822 7839 3-10-5 765 599246 2588 2605 Exon18 CAATCCCACGCCCCTGTC 21 7823 7840 3-10-5 766 599247 2589 2606 Exon18 TCAATCCCACGCCCCTGT 61 7824 7841 3-10-5 767 599248 2590 2607 Exon18 TTCAATCCCACGCCCCTG 51 7825 7842 3-10-5 768 599249 2591 2608 Exon18 ATTCAATCCCACGCCCCT 58 7826 7843 3-10-5 769 599250 2592 2609 Exon18 AATTCAATCCCACGCCCC 49 7827 7844 3-10-5 770 599251 2593 2610 Exon18 TAATTCAATCCCACGCCC 46 7828 7845 3-10-5 771 599252 2594 2611 Exon18 TTAATTCAATCCCACGCC 32 7829 7846 3-10-5 772 599253 2595 2612 Exon18 TTTAATTCAATCCCACGC 23 7830 7847 3-10-5 773 599254 2596 2613 Exon18 TTTTAATTCAATCCCACG 0 7831 7848 3-10-5 774 599255 2597 2614 Exon18 GTTTTAATTCAATCCCAC 61 7832 7849 3-10-5 775 599256 2598 2615 Exon18 TGTTTTAATTCAATCCCA 64 7833 7850 3-10-5 776 599257 2599 2616 Exon18 CTGTTTTAATTCAATCCC 66 7834 7851 3-10-5 777 599258 2600 2617 Exon18 GCTGTTTTAATTCAATCC 59 7835 7852 3-10-5 778 599259 2601 2618 Exon18 AGCTGTTTTAATTCAATC 40 7836 7853 3-10-5 779 599260 2602 2619 Exon18 CAGCTGTTTTAATTCAAT 38 7837 7854 3-10-5 780 599261 2603 2620 Exon18 GCAGCTGTTTTAATTCAA 54 7838 7855 3-10-5 781 599509 2552 2570 Exon18 TAGAAAACCCAAATCCTCA 54 7787 7805 6-7-6 681 599273 2553 2571 Exon18 ATAGAAAACCCAAATCCTC 0 7788 7806 6-7-6 682 599274 2554 2572 Exon18 TATAGAAAACCCAAATCCT 57 7789 7807 6-7-6 683 599275 2556 2574 Exon18 CTTATAGAAAACCCAAATC 0 7791 7809 6-7-6 684 599276 2557 2575 Exon18 CCTTATAGAAAACCCAAAT 44 7792 7810 6-7-6 685 599277 2558 2576 Exon18 CCCTTATAGAAAACCCAAA 0 7793 7811 6-7-6 686 599278 2559 2577 Exon18 CCCCTTATAGAAAACCCAA 0 7794 7812 6-7-6 687 599279 2560 2578 Exon18 ACCCCTTATAGAAAACCCA 20 7795 7813 6-7-6 688 599280 2561 2579 Exon18 AACCCCTTATAGAAAACCC 70 7796 7814 6-7-6 689 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 85 7839 7858 5-10-5 317 599262 2604 2621 Exon18 CGCAGCTGTTTTAATTCA 49 7839 7856 3-10-5 782 599263 2605 2622 Exon18 TCGCAGCTGTTTTAATTC 49 7840 7857 3-10-5 783 599264 2606 2623 Exon18 GTCGCAGCTGTTTTAATT 62 7841 7858 3-10-5 784 599265 2607 2624 Exon18 TGTCGCAGCTGTTTTAAT 63 7842 7859 3-10-5 792 599266 2608 2625 Exon18 TTGTCGCAGCTGTTTTAA 41 7843 7860 3-10-5 793 599267 2609 2626 Exon18 GTTGTCGCAGCTGTTTTA 52 7844 7861 3-10-5 794 599268 2610 2627 Exon18 TGTTGTCGCAGCTGTTTT 51 7845 7862 3-10-5 795 599269 2611 2628 Exon18/ TTGTTGTCGCAGCTGTTT 58 n/a n/a 3-10-5 796 Repeat 599270 2612 2629 Exon18/ TTTGTTGTCGCAGCTGTT 69 n/a n/a 3-10-5 797 Repeat 599271 2613 2630 Exon18/ TTTTGTTGTCGCAGCTGT 69 n/a n/a 3-10-5 798 Repeat 599272 2614 2631 Exon18/ TTTTTGTTGTCGCAGCTG 72 n/a n/a 3-10-5 799 Repeat 599205 2607 2624 Exon18 TGTCGCAGCTGTTTTAAT 54 7842 7859 5-8-5 792 599206 2608 2625 Exon18 TTGTCGCAGCTGTTTTAA 62 7843 7860 5-8-5 793 599207 2609 2626 Exon18 GTTGTCGCAGCTGTTTTA 62 7844 7861 5-8-5 794 599208 2610 2627 Exon18 TGTTGTCGCAGCTGTTTT 66 7845 7862 5-8-5 795 599209 2611 2628 Exon18/ TTGTTGTCGCAGCTGTTT 60 n/a n/a 5-8-5 796 Repeat 599210 2612 2629 Exon18/ TTTGTTGTCGCAGCTGTT 62 n/a n/a 5-8-5 797 Repeat 599211 2613 2630 Exon18/ TTTTGTTGTCGCAGCTGT 65 n/a n/a 5-8-5 798 Repeat 599212 2614 2631 Exon18/ TTTTTGTTGTCGCAGCTG 67 n/a n/a 5-8-5 799 Repeat

TABLE-US-00025 TABLE24 InhibitionofCFBmRNAby5-10-5MOEgapmerstargetingSEQIDNO:1orSEQIDNO:2 SEQ SEQ SEQ SEQ ID ID ID ID NO:1 NO:1 % NO:2 NO:2 SEQ ISIS start stop Target in- start stop ID NO site site region Sequence hibition site site NO: 588570 150 169 Exon1 TGGTCACATTCCCTTCCCCT 72 1871 1890 396 588571 152 171 Exon1 CCTGGTCACATTCCCTTCCC 80 1873 1892 397 532614 154 173 Exon1 GACCTGGTCACATTCCCTTC 65 1875 1894 12 588572 156 175 Exon1 TAGACCTGGTCACATTCCCT 74 1877 1896 398 588573 158 177 Exon1 CCTAGACCTGGTCACATTCC 72 1879 1898 399 588566 2189 2208 Exon15 CCTTCCGAGTCAGCTTTTTC 66 6977 6996 400 588567 2191 2210 Exon15 CTCCTTCCGAGTCAGCTTTT 66 6979 6998 401 532770 2193 2212 Exon15 ACCTCCTTCCGAGTCAGCTT 64 6981 7000 198 588568 2195 2214 Exon15 AGACCTCCTTCCGAGTCAGC 78 6983 7002 402 588569 2197 2216 Exon15 GTAGACCTCCTTCCGAGTCA 74 6985 7004 403 588574 2453 2472 Exon18 TTTGCCGCTTCTGGTTTTTG 71 7688 7707 404 588575 2455 2474 Exon18 CTTTTGCCGCTTCTGGTTTT 72 7690 7709 405 532800 2457 2476 Exon18 TGCTTTTGCCGCTTCTGGTT 71 7692 7711 228 588576 2459 2478 Exon18 CCTGCTTTTGCCGCTTCTGG 59 7694 7713 406 588577 2461 2480 Exon18 TACCTGCTTTTGCCGCTTCT 76 7696 7715 407 516350 2550 2569 Exon18 AGAAAACCCAAATCCTCATC 58 7785 7804 408 588509 2551 2570 Exon18 TAGAAAACCCAAATCCTCAT 6 7786 7805 409 588510 2552 2571 Exon18 ATAGAAAACCCAAATCCTCA 10 7787 7806 410 588511 2553 2572 Exon18 TATAGAAAACCCAAATCCTC 9 7788 7807 411 588512 2554 2573 Exon18 TTATAGAAAACCCAAATCCT 80 7789 7808 412 588513 2555 2574 Exon18 CTTATAGAAAACCCAAATCC 70 7790 7809 413 588514 2556 2575 Exon18 CCTTATAGAAAACCCAAATC 71 7791 7810 414 588515 2557 2576 Exon18 CCCTTATAGAAAACCCAAAT 78 7792 7811 415 588516 2558 2577 Exon18 CCCCTTATAGAAAACCCAAA 72 7793 7812 416 588517 2559 2578 Exon18 ACCCCTTATAGAAAACCCAA 80 7794 7813 417 588518 2560 2579 Exon18 AACCCCTTATAGAAAACCCA 80 7795 7814 418 588519 2561 2580 Exon18 AAACCCCTTATAGAAAACCC 62 7796 7815 419 588520 2562 2581 Exon18 GAAACCCCTTATAGAAAACC 59 7797 7816 420 588521 2563 2582 Exon18 GGAAACCCCTTATAGAAAAC 40 7798 7817 421 588522 2564 2583 Exon18 AGGAAACCCCTTATAGAAAA 66 7799 7818 422 588523 2565 2584 Exon18 CAGGAAACCCCTTATAGAAA 63 7800 7819 423 588524 2566 2585 Exon18 GCAGGAAACCCCTTATAGAA 70 7801 7820 424 588525 2567 2586 Exon18 AGCAGGAAACCCCTTATAGA 67 7802 7821 425 588526 2568 2587 Exon18 CAGCAGGAAACCCCTTATAG 0 7803 7822 426 588527 2569 2588 Exon18 CCAGCAGGAAACCCCTTATA 11 7804 7823 427 588528 2570 2589 Exon18 TCCAGCAGGAAACCCCTTAT 15 7805 7824 428 532809 2571 2590 Exon18 GTCCAGCAGGAAACCCCTTA 75 7806 7825 237 588529 2572 2591 Exon18 TGTCCAGCAGGAAACCCCTT 16 7807 7826 429 588530 2573 2592 Exon18 CTGTCCAGCAGGAAACCCCT 16 7808 7827 430 588531 2574 2593 Exon18 CCTGTCCAGCAGGAAACCCC 19 7809 7828 431 588532 2575 2594 Exon18 CCCTGTCCAGCAGGAAACCC 15 7810 7829 432 588533 2576 2595 Exon18 CCCCTGTCCAGCAGGAAACC 29 7811 7830 433 532810 2577 2596 Exon18 GCCCCTGTCCAGCAGGAAAC 74 7812 7831 238 588534 2578 2597 Exon18 CGCCCCTGTCCAGCAGGAAA 21 7813 7832 434 588535 2579 2598 Exon18 ACGCCCCTGTCCAGCAGGAA 16 7814 7833 435 588536 2580 2599 Exon18 CACGCCCCTGTCCAGCAGGA 0 7815 7834 436 588537 2581 2600 Exon18 CCACGCCCCTGTCCAGCAGG 8 7816 7835 437 588538 2582 2601 Exon18 CCCACGCCCCTGTCCAGCAG 10 7817 7836 438 588539 2583 2602 Exon18 TCCCACGCCCCTGTCCAGCA 23 7818 7837 439 588540 2584 2603 Exon18 ATCCCACGCCCCTGTCCAGC 16 7819 7838 440 588541 2585 2604 Exon18 AATCCCACGCCCCTGTCCAG 16 7820 7839 441 588542 2586 2605 Exon18 CAATCCCACGCCCCTGTCCA 12 7821 7840 442 588543 2587 2606 Exon18 TCAATCCCACGCCCCTGTCC 26 7822 7841 443 588544 2588 2607 Exon18 TTCAATCCCACGCCCCTGTC 26 7823 7842 444 588545 2589 2608 Exon18 ATTCAATCCCACGCCCCTGT 31 7824 7843 445 588546 2590 2609 Exon18 AATTCAATCCCACGCCCCTG 22 7825 7844 446 588547 2591 2610 Exon18 TAATTCAATCCCACGCCCCT 12 7826 7845 447 588548 2592 2611 Exon18 TTAATTCAATCCCACGCCCC 20 7827 7846 448 588549 2593 2612 Exon18 TTTAATTCAATCCCACGCCC 26 7828 7847 449 588550 2594 2613 Exon18 TTTTAATTCAATCCCACGCC 32 7829 7848 450 588551 2595 2614 Exon18 GTTTTAATTCAATCCCACGC 48 7830 7849 451 588552 2596 2615 Exon18 TGTTTTAATTCAATCCCACG 57 7831 7850 452 588553 2597 2616 Exon18 CTGTTTTAATTCAATCCCAC 49 7832 7851 453 588554 2598 2617 Exon18 GCTGTTTTAATTCAATCCCA 64 7833 7852 454 532811 2599 2618 Exon18 AGCTGTTTTAATTCAATCCC 78 7834 7853 239 588555 2600 2619 Exon18 CAGCTGTTTTAATTCAATCC 48 7835 7854 455 588556 2601 2620 Exon18 GCAGCTGTTTTAATTCAATC 55 7836 7855 456 588557 2602 2621 Exon18 CGCAGCTGTTTTAATTCAAT 51 7837 7856 457 588558 2603 2622 Exon18 TCGCAGCTGTTTTAATTCAA 51 7838 7857 458 532917 2604 2623 Exon18 GTCGCAGCTGTTTTAATTCA 82 7839 7858 317 588559 2605 2624 Exon18 TGTCGCAGCTGTTTTAATTC 58 7840 7859 459 588560 2606 2625 Exon18 TTGTCGCAGCTGTTTTAATT 72 7841 7860 460 588561 2607 2626 Exon18 GTTGTCGCAGCTGTTTTAAT 75 7842 7861 461 532952 2608 2627 Exon18 TGTTGTCGCAGCTGTTTTAA 39 7843 7862 395 588562 2609 2628 Exon18/ TTGTTGTCGCAGCTGTTTTA 53 n/a n/a 462 Repeat 588563 2610 2629 Exon18/ TTTGTTGTCGCAGCTGTTTT 62 n/a n/a 463 Repeat 588564 2611 2630 Exon18/ TTTTGTTGTCGCAGCTGTTT 63 n/a n/a 464 Repeat 588565 2612 2631 Exon18/ TTTTTGTTGTCGCAGCTGTT 64 n/a n/a 465 Repeat

Example 8: Dose-Dependent Antisense Inhibition of Human CFB in HepG2 Cells by 5-10-5 MOE Gapmers

[0459] Gapmers from studies described above exhibiting in vitro inhibition of CFB mRNA were selected and tested at various doses in HepG2 cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.313 ?M, 0.625 ?M, 1.25 ?M, 2.50 UM, 5.00 UM, or 10.00 ?M concentrations of antisense oligonucleotide, as specified in the Table below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0460] The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented. CFB mRNA levels were reduced in a dose-dependent manner in antisense oligonucleotide treated cells.

TABLE-US-00026 TABLE 25 0.313 0.625 1.25 2.50 5.00 10.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532614 7 13 43 72 65 71 2.2 532635 12 0 3 28 0 0 >10 532692 26 0 12 52 55 74 3.7 532770 21 18 32 73 64 88 1.8 532775 8 0 26 35 47 59 6.2 532800 0 5 30 65 50 75 3.1 532809 12 30 28 40 46 66 4.6 532810 28 44 32 69 84 95 1.2 532811 66 83 90 94 97 99 <0.3 532917 64 85 88 96 97 99 <0.3 532952 50 53 68 80 91 94 0.4

Example 9: Dose-Dependent Antisense Inhibition of Human CFB in HepG2 Cells

[0461] Gapmers from studies described above exhibiting in vitro inhibition of CFB mRNA were selected and tested at various doses in HepG2 cells. The antisense oligonucleotides were tested in a number of experiments with similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.08 ?M, 0.25 ?M, 0.74 M, 2.22 ?M, 6.67 ?M, and 20.00 ?M concentrations of antisense oligonucleotide, as specified in the Table below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0462] The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented. CFB mRNA levels were reduced in a dose-dependent manner in antisense oligonucleotide treated cells.

TABLE-US-00027 TABLE 26 0.08 0.25 0.74 2.22 6.67 20.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532811 19 53 81 87 96 97 0.2 588834 7 42 64 92 98 98 0.5 588835 11 30 66 89 97 97 0.5 588836 14 40 61 91 97 97 0.5 588837 6 39 67 89 96 97 0.5 588838 0 27 41 81 87 97 1.0 588842 17 51 68 86 93 95 0.3 588843 21 38 72 90 95 96 0.4 588870 9 31 56 88 95 97 0.6 588871 14 25 47 79 93 97 0.7 588872 18 28 59 84 92 97 0.6

TABLE-US-00028 TABLE 27 0.08 0.25 0.74 2.22 6.67 20.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532811 31 70 89 94 97 97 0.1 588844 31 60 77 91 95 96 0.1 588846 32 52 78 89 95 97 0.2 588847 22 52 77 91 95 97 0.2 588848 20 40 73 91 96 98 0.3 588851 40 52 82 94 97 97 0.1 588854 17 55 59 84 94 96 0.4 588855 10 32 56 82 93 96 0.6 588856 13 46 75 90 96 97 0.3 588857 11 52 73 94 96 97 0.3 588858 19 48 75 94 97 98 0.3

TABLE-US-00029 TABLE 28 0.08 0.25 0.74 2.22 6.67 20.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532811 42 66 88 96 97 98 0.1 588859 18 46 66 90 96 97 0.4 588860 55 80 94 97 97 97 <0.1 588861 24 61 86 93 96 97 0.2 588862 25 64 85 94 96 98 0.1 588863 50 73 89 96 96 98 <0.1 588864 52 80 92 96 98 98 <0.1 588865 46 72 91 96 96 99 <0.1 588866 47 76 88 96 97 98 <0.1 588867 43 69 83 92 96 99 0.1 588868 43 56 65 84 93 97 0.1

TABLE-US-00030 TABLE 29 0.08 0.25 0.74 2.22 6.67 20.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532810 0 14 38 72 89 96 1.2 532811 18 54 79 93 96 97 0.3 532952 19 34 73 87 94 96 0.4 588534 17 13 44 77 93 97 0.9 588544 12 43 69 86 89 93 0.4 588545 17 55 67 86 91 93 0.3 588546 10 32 67 85 91 93 0.6 588552 27 54 76 90 94 97 0.2 588553 32 68 87 93 95 97 0.1 588560 16 54 76 90 94 96 0.3 588561 18 45 68 85 93 96 0.4

TABLE-US-00031 TABLE 30 0.08 0.25 0.74 2.22 6.67 20.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532811 22 60 82 94 97 98 0.2 588536 2 38 65 90 96 97 0.6 588537 12 38 63 87 94 97 0.5 588547 19 35 61 86 93 97 0.5 588548 19 36 75 88 95 96 0.4 588554 0 76 92 95 97 97 <0.1 588555 31 61 89 96 97 98 0.1 588556 33 56 82 95 94 97 0.1 588562 12 39 71 87 94 97 0.4 588563 25 48 72 86 94 96 0.3 588564 15 33 63 89 91 97 0.5

TABLE-US-00032 TABLE 31 0.08 0.25 0.74 2.22 6.67 20.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M (?M) 532811 39 68 86 96 98 98 0.1 588538 0 40 82 94 97 98 0.3 588539 34 65 88 95 98 98 0.1 588540 30 51 81 91 97 98 0.2 588549 31 57 82 95 96 98 0.1 588550 34 65 88 96 98 98 0.1 588551 47 66 87 96 98 99 <0.1 588557 40 84 95 98 98 98 <0.1 588558 45 73 93 97 98 99 <0.1 588559 51 69 83 96 98 99 <0.1 588565 19 56 81 92 96 98 0.2

Example 10: Dose-Dependent Antisense Inhibition of Human CFB in HepG2 Cells

[0463] Gapmers from studies described above exhibiting in vitro inhibition of CFB mRNA were selected and tested at various doses in HepG2 cells. The antisense oligonucleotides were tested in a number of experiments with similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.06 ?M, 0.25 ?M, 1.00 ?M, and 4.00 ?M concentrations of antisense oligonucleotide, as specified in the Table below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0464] The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented. CFB mRNA levels were reduced in a dose-dependent manner in antisense oligonucleotide treated cells.

TABLE-US-00033 TABLE 32 ISIS 0.06 0.25 1.00 4.00 IC.sub.50 No ?M ?M ?M ?M (?M) 532917 31 58 87 92 0.2 588860 18 50 79 93 0.3 599001 16 28 69 90 0.5 599024 14 32 74 90 0.4 599025 0 31 56 92 0.7 599032 28 44 62 88 0.3 599033 28 46 80 92 0.2 599077 8 20 59 80 0.8 599080 9 33 48 76 0.9 599086 7 22 53 83 0.8 599087 21 31 74 87 0.4 599088 13 37 69 82 0.5 599089 3 36 55 79 0.7 599093 25 59 79 88 0.2 599094 19 29 75 89 0.4 599095 29 43 67 87 0.3 599096 23 51 70 88 0.3 599149 20 53 82 92 0.3 599188 0 21 62 85 0.8

TABLE-US-00034 TABLE 33 ISIS 0.06 0.25 1.00 4.00 IC.sub.50 No ?M ?M ?M ?M (?M) 532917 0 42 81 91 0.4 588860 17 49 74 92 0.3 599155 29 52 67 87 0.3 599198 3 25 64 89 0.6 599201 13 26 67 91 0.5 599202 0 44 72 87 0.5 599203 22 41 75 88 0.3 599314 12 34 71 84 0.5 599316 7 37 66 88 0.5 599317 8 1 54 83 1.0 599321 8 33 70 85 0.5 599322 24 38 66 87 0.4 599327 22 32 66 89 0.4 599328 0 31 59 88 0.7 599330 5 43 67 84 0.5 599374 23 42 80 91 0.3 599378 21 57 80 93 0.2 599380 23 56 82 93 0.2 599432 17 37 73 93 0.4

TABLE-US-00035 TABLE 34 ISIS 0.06 0.25 1.00 4.00 IC.sub.50 No ?M ?M ?M ?M (?M) 532917 23 65 76 93 0.2 588860 17 60 76 90 0.3 601282 48 68 81 88 0.1 601269 18 59 80 94 0.2 601276 34 64 81 91 0.1 601275 14 39 78 90 0.4 601344 52 84 92 94 <0.06 601383 53 81 86 94 <0.06 601382 41 76 88 94 0.1 601385 52 74 89 91 <0.06 601332 41 69 86 94 0.1 601345 36 75 86 95 0.1 601371 34 72 91 93 0.1 601384 50 78 91 95 <0.06 601380 28 57 83 92 0.2 601387 48 61 82 88 0.1 601341 28 65 83 91 0.2 601346 31 69 82 93 0.1 601335 24 56 85 92 0.2

TABLE-US-00036 TABLE 35 ISIS 0.06 0.25 1.00 4.00 IC.sub.50 No ?M ?M ?M ?M (?M) 532917 31 66 86 93 0.1 588860 28 62 85 94 0.2 599208 24 50 71 89 0.3 599261 31 49 81 94 0.2 599267 41 48 80 88 0.2 599268 28 56 75 92 0.2 599313 14 24 71 92 0.5 599441 24 57 80 87 0.2 599494 13 55 86 94 0.3 599552 30 69 93 95 0.1 599553 34 71 93 96 0.1 599554 30 74 93 96 0.1 599568 40 77 90 97 0.1 599570 61 82 93 96 <0.06 599577 18 62 81 93 0.2 599581 27 60 80 94 0.2 599591 49 74 93 96 <0.06 599592 46 76 90 94 0.1 599593 44 72 91 95 0.1

TABLE-US-00037 TABLE 36 ISIS 0.06 0.25 1.00 4.00 IC.sub.50 No ?M ?M ?M ?M (?M) 532917 25 56 84 92 0.2 588860 11 51 80 92 0.3 599547 23 60 82 90 0.2 599569 42 73 85 88 0.1 599578 29 49 82 89 0.2 599582 21 56 78 91 0.2 599590 24 62 80 90 0.2 601209 21 49 85 88 0.3 601210 34 64 86 92 0.1 601212 46 68 88 90 0.1 601213 54 80 90 92 <0.06 601214 38 77 88 95 0.1 601215 42 64 85 92 0.1 601216 45 57 76 89 0.1 601264 29 58 86 95 0.2 601278 51 82 83 93 <0.06 601279 44 80 92 96 0.1 601280 44 73 87 94 0.1 601281 51 80 91 94 <0.06

Example 11: Dose-Dependent Antisense Inhibition of Human CFB in HepG2 Cells

[0465] Gapmers from studies described above exhibiting in vitro inhibition of CFB mRNA were selected and tested at various doses in HepG2 cells. Additionally, a deoxy, MOE and cEt oligonucleotide, ISIS 594430, was designed with the same sequence (CTCCTTCCGAGTCAGC, SEQ ID NO: 549) and target region (target start site 2195 of SEQ ID NO: 1 and target start site 6983 of SED ID NO: 2) as ISIS 588870, another deoxy, MOE, and cEt oligonucleotide. ISIS 594430 is a 3-10-3 cEt gapmer.

[0466] Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.01 ?M, 0.04 ?M, 0.12 ?M, 0.37 ?M, 1.11 ?M, 3.33 ?M, and 10.00 ?M concentrations of antisense oligonucleotide, as specified in the Table below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and CFB mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3459 was used to measure mRNA levels. CFB mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN?. Results are presented as percent inhibition of CFB, relative to untreated control cells.

[0467] The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented. CFB mRNA levels were reduced in a dose-dependent manner in antisense oligonucleotide treated cells.

TABLE-US-00038 TABLE 37 0.01 0.04 0.12 0.37 1.11 3.33 10.00 IC.sub.50 ISIS No ?M ?M ?M ?M ?M ?M ?M (?M) 588536 0 0 0 5 45 73 94 1.4 588548 0 0 0 19 52 78 90 1.2 588553 0 0 9 42 76 85 94 0.6 588555 0 52 23 58 78 83 95 0.3 588847 4 1 18 45 67 84 96 0.5 588848 0 3 13 38 67 83 95 0.6 594430 0 0 10 34 50 55 84 1.4

Example 12: Tolerability of MOE Gapmers Targeting Human CFB in CD1 Mice

[0468] CD1? mice (Charles River, MA) are a multipurpose mouse model, frequently utilized for safety and efficacy testing. The mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Study 1 (with 5-10-5 MOE Gapmers)

[0469] Groups of seven-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 100 mg/kg of ISIS oligonucleotide. A group of male CD1 mice was injected subcutaneously once a week for 6 weeks with PBS. One group of mice was injected with subcutaneously once a week for 6 weeks with 100 mg/kg of control oligonucleotide ISIS 141923 (CCTTCCCTGAAGGTTCCTCC, designated herein as SEQ ID NO: 809, 5-10-5 MOE gapmer with no known murine target). Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0470] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00039 TABLE 38 Plasma chemistry markers in CD1 mice plasma on day 40 ALT AST BUN (IU/L) (IU/L) (mg/dL) PBS 25 46 20 ISIS 532614 513 407 22 ISIS 532692 131 130 24 ISIS 532770 36 53 25 ISIS 532775 193 158 23 ISIS 532800 127 110 25 ISIS 532809 36 42 22 ISIS 532810 229 286 26 ISIS 532811 197 183 21 ISIS 532917 207 204 27 ISIS 532952 246 207 25 ISIS 141923 39 67 23

Weights

[0471] Body weights of the mice were measured on day 40 before sacrificing the mice. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00040 TABLE 39 Weights (g) of CD1 mice on day 40 Body Kidney Liver Spleen PBS 44 0.8 2.0 0.1 ISIS 532614 43 0.7 4.3 0.2 ISIS 532692 42 0.7 2.6 0.2 ISIS 532770 42 0.6 2.3 0.2 ISIS 532775 42 0.7 2.5 0.2 ISIS 532800 43 0.6 2.8 0.3 ISIS 532809 42 0.6 2.2 0.1 ISIS 532810 43 0.6 2.3 0.2 ISIS 532811 41 0.7 2.4 0.2 ISIS 532917 42 0.7 3.0 0.2 ISIS 532952 44 0.8 2.5 0.3 ISIS 141923 41 0.6 2.0 0.1
Study 2 (with 5-10-5 MOE Gapmers)

[0472] Groups of six- to eight-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 100 mg/kg of ISIS oligonucleotide. Two groups of male CD1 mice were injected subcutaneously once a week for 6 weeks with PBS. One group of mice was injected with subcutaneously once a week for 6 weeks with 100 mg/kg of control oligonucleotide ISIS 141923. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0473] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00041 TABLE 40 Plasma chemistry markers in CD1 mice plasma on day 45 ALT AST Albumin BUN (IU/L) (IU/L) (g/dL) (mg/dL) PBS 39 53 2.9 29 PBS 50 97 2.9 30 ISIS 141923 163 174 4.1 25 ISIS 532810 321 297 2.5 26 ISIS 532952 182 199 2.7 27 ISIS 588534 276 248 2.6 29 ISIS 588536 48 60 2.9 31 ISIS 588537 72 79 4.0 25 ISIS 588538 63 67 4.5 29 ISIS 588539 238 177 3.9 28 ISIS 588545 496 256 4.4 24 ISIS 588547 323 210 4.4 25 ISIS 588548 61 63 4.2 27 ISIS 588549 127 132 4.1 23 ISIS 588551 302 282 4.2 22 ISIS 588552 76 98 4.0 30 ISIS 588558 1066 521 3.9 27 ISIS 588559 76 94 4.1 26 ISIS 588561 502 500 4.4 26 ISIS 588563 50 99 4.4 28

Weights

[0474] Body weights of the mice were measured on day 42. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 45. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00042 TABLE 41 Weights (g) of CD1 mice on day 40 Body Kidney Liver Spleen PBS 44 0.7 2.4 0.1 PBS 43 0.7 2.4 0.2 ISIS 141923 43 0.6 2.4 0.2 ISIS 532810 41 0.6 1.9 0.1 ISIS 532952 43 0.6 2.4 0.2 ISIS 588534 44 0.7 2.8 0.2 ISIS 588536 43 0.7 2.7 0.2 ISIS 588537 43 0.7 2.4 0.2 ISIS 588538 44 0.7 2.8 0.2 ISIS 588539 44 0.6 2.7 0.2 ISIS 588545 44 0.8 3.3 0.3 ISIS 588547 42 0.6 3.3 0.3 ISIS 588548 43 0.6 2.8 0.2 ISIS 588549 42 0.6 2.8 0.3 ISIS 588551 39 0.6 2.2 0.2 ISIS 588552 41 0.6 2.2 0.2 ISIS 588558 44 0.7 3.3 0.3 ISIS 588559 43 0.6 2.7 0.3 ISIS 588561 40 0.7 2.4 0.3 ISIS 588563 41 0.7 2.4 0.2
Study 3 (with 5-10-5 MOE Gapmers)

[0475] Groups of six- to eight-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 100 mg/kg of ISIS oligonucleotide. Two groups of male CD1 mice were injected subcutaneously once a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0476] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00043 TABLE 42 Plasma chemistry markers in CD1 mice plasma on day 42 ALT AST Albumin BUN (IU/L) (IU/L) (g/dL) (mg/dL) PBS 37 108 3.1 30 PBS 45 51 3.0 27 ISIS 588544 209 168 2.9 26 ISIS 588546 526 279 3.0 22 ISIS 588550 82 136 2.7 25 ISIS 588553 79 105 3.0 24 ISIS 588554 112 220 3.2 19 ISIS 588555 95 162 2.8 25 ISIS 588556 345 236 3.0 26 ISIS 588557 393 420 2.8 24 ISIS 588560 109 148 2.7 27 ISIS 588562 279 284 2.8 22 ISIS 588564 152 188 3.0 23 ISIS 588565 247 271 2.8 28

Weights

[0477] Body weights of the mice were measured on day 42. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 42. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00044 TABLE 43 Weights (g) of CD1 mice on day 40 Body Kidney Liver Spleen PBS 42 0.7 2.4 0.1 PBS 41 0.7 2.4 0.2 ISIS 588544 44 0.6 1.9 0.1 ISIS 588546 43 0.6 2.4 0.2 ISIS 588550 41 0.7 2.8 0.2 ISIS 588553 44 0.7 2.7 0.2 ISIS 588554 40 0.7 2.4 0.2 ISIS 588555 44 0.7 2.8 0.2 ISIS 588556 39 0.6 2.7 0.2 ISIS 588557 41 0.8 3.3 0.3 ISIS 588560 38 0.6 3.2 0.3 ISIS 588562 41 0.6 2.8 0.2 ISIS 588564 40 0.6 2.8 0.3 ISIS 588565 39 0.6 2.2 0.2
Study 4 (with (S) cEt Gapmers and Deoxy, MOE and cEt Oligonucleotides)

[0478] Groups of ten-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 50 mg/kg of ISIS oligonucleotide from the studies described above. In addition, two oligonucleotides, ISIS 594431 and ISIS 594432, were designed as 3-10-3 cEt gapmers and were also tested in this study. ISIS 594431(ACCTCCTTCCGAGTCA, SEQ ID NO: 550) targets the same region as ISIS 588871, a deoxy, MOE and cEt gapmer (target start site 2197 of SEQ ID NO: 1 and target start site 6985 of SEQ ID NO: 2). ISIS 594432 (TGGTCACATTCCCTTC, SEQ ID NO: 542) targets the same region as ISIS 588872, a deoxy, MOE and cEt gapmer (target start site 154 of SEQ ID NO: 1 and target start site 1875 of SEQ ID NO: 2).

[0479] Two groups of male CD1 mice were injected subcutaneously once a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0480] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00045 TABLE 44 Plasma chemistry markers in CD1 mice plasma on day 42 ALT AST Albumin Creatinine BUN Chemistry (IU/L) (IU/L) (g/dL) (mg/dL) (mg/dL) PBS 71 77 2.7 0.2 29 PBS 30 36 2.7 0.2 26 ISIS 588834 Deoxy, MOE and cEt 436 510 2.8 0.2 25 ISIS 588835 Deoxy, MOE and cEt 70 98 3.0 0.2 27 ISIS 588836 Deoxy, MOE and cEt 442 312 2.7 0.2 27 ISIS 588846 Deoxy, MOE and cEt 50 75 2.5 0.1 28 ISIS 588847 Deoxy, MOE and cEt 44 71 2.6 0.1 24 ISIS 588848 Deoxy, MOE and cEt 47 70 2.4 0.1 27 ISIS 588857 Deoxy, MOE and cEt 1287 655 2.7 0.2 26 ISIS 588858 Deoxy, MOE and cEt 1169 676 2.5 0.2 26 ISIS 588859 Deoxy, MOE and cEt 1036 1300 3.2 0.2 25 ISIS 588861 Deoxy, MOE and cEt 749 466 3.1 0.1 24 ISIS 588862 Deoxy, MOE and cEt 1564 1283 2.9 0.2 22 ISIS 588863 Deoxy, MOE and cEt 477 362 2.8 0.1 23 ISIS 588864 Deoxy, MOE and cEt 118 165 2.9 0.2 27 ISIS 588866 Deoxy, MOE and cEt 843 784 3.2 0.2 25 ISIS 594430 3-10-3 cEt 89 99 2.4 0.1 28 ISIS 594431 3-10-3 cEt 590 433 3.0 0.2 24 ISIS 594432 3-10-3 cEt 2595 2865 2.4 0.1 25

Weights

[0481] Body weights of the mice were measured on day 39. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 42. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00046 TABLE 45 Weights (g) of CD1 mice Chemistry Body Kidney Liver Spleen PBS 37 0.6 2.1 0.1 PBS 45 0.7 2.5 0.2 ISIS 588834 Deoxy, MOE and cEt 40 0.6 3.2 0.2 ISIS 588835 Deoxy, MOE and cEt 38 0.7 2.8 0.3 ISIS 588836 Deoxy, MOE and cEt 41 0.7 2.3 0.2 ISIS 588837 Deoxy, MOE and cEt 38 0.6 2.4 0.3 ISIS 588846 Deoxy, MOE and cEt 39 0.6 2.3 0.2 ISIS 588847 Deoxy, MOE and cEt 40 0.7 2.5 0.2 ISIS 588848 Deoxy, MOE and cEt 43 0.7 2.6 0.3 ISIS 588857 Deoxy, MOE and cEt 39 0.6 3.3 0.2 ISIS 588858 Deoxy, MOE and cEt 37 0.6 3.4 0.2 ISIS 588859 Deoxy, MOE and cEt 41 0.7 2.5 0.3 ISIS 588861 Deoxy, MOE and cEt 39 0.6 2.6 0.4 ISIS 588862 Deoxy, MOE and cEt 34 0.6 2.5 0.4 ISIS 588863 Deoxy, MOE and cEt 40 0.6 2.7 0.3 ISIS 588864 Deoxy, MOE and cEt 40 0.7 2.3 0.2 ISIS 588866 Deoxy, MOE and cEt 45 0.7 3.0 0.2 ISIS 594430 3-10-3 cEt 39 0.6 2.2 0.2 ISIS 594431 3-10-3 cEt 36 0.6 3.2 0.2 ISIS 594432 3-10-3 cEt 31 0.4 1.9 0.1
Study 5 (with MOE Gapmers, (S) cEt Gapmers and Deoxy, MOE and cEt Oligonucleotides)

[0482] Groups of eight- to nine-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 50 mg/kg of ISIS oligonucleotide. Two groups of male CD1 mice were injected subcutaneously once a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0483] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00047 TABLE 46 Plasma chemistry markers in CD1 mice plasma on day 42 ALT AST Albumin Creatinine BUN Chemistry (IU/L) (IU/L) (g/dL) (mg/dL) (mg/dL) PBS 33 84 2.9 0.2 28 PBS 32 65 2.5 0.1 27 ISIS 532692 5-10-5 MOE 363 281 3.0 0.2 30 ISIS 532770 5-10-5 MOE 69 100 2.9 0.1 28 ISIS 532775 5-10-5 MOE 371 333 2.6 0.1 29 ISIS 532800 5-10-5 MOE 104 106 2.7 0.1 31 ISIS 532809 5-10-5 MOE 69 127 2.8 0.1 26 ISIS 588540 5-10-5 MOE 66 110 2.8 0.1 26 ISIS 588838 3-10-3 cEt 391 330 2.9 0.1 25 ISIS 588842 Deoxy, MOE and cEt 224 264 2.6 0.1 26 ISIS 588843 3-10-3 cEt 185 160 2.8 0.1 24 ISIS 588844 Deoxy, MOE and cEt 304 204 2.7 0.1 25 ISIS 588851 Deoxy, MOE and cEt 186 123 2.7 0.1 31 ISIS 588854 Deoxy, MOE and cEt 1232 925 2.7 0.1 25 ISIS 588855 Deoxy, MOE and cEt 425 321 2.7 0.1 28 ISIS 588856 Deoxy, MOE and cEt 78 101 2.4 0.1 31 ISIS 588865 Deoxy, MOE and cEt 126 145 2.5 0.1 23 ISIS 588867 Deoxy, MOE and cEt 108 112 2.5 0.1 32 ISIS 588868 Deoxy, MOE and cEt 61 124 2.5 0.1 28 ISIS 588870 Deoxy, MOE and cEt 48 69 2.4 0.1 31 ISIS 588871 Deoxy, MOE and cEt 723 881 2.5 0.1 24 ISIS 588872 Deoxy, MOE and cEt 649 654 2.7 0.1 26

Weights

[0484] Body weights of the mice were measured on day 40. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 42. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00048 TABLE 47 Weights (g) of CD1 mice Chemistry Body Kidney Liver Spleen PBS 46 0.7 2.3 0.2 PBS 44 0.7 2.3 0.2 ISIS 532692 5-10-5 MOE 44 0.6 2.8 0.2 ISIS 532770 5-10-5 MOE 43 0.6 2.2 0.2 ISIS 532775 5-10-5 MOE 43 0.6 2.8 0.2 ISIS 532800 5-10-5 MOE 47 0.7 2.9 0.2 ISIS 532809 5-10-5 MOE 44 0.7 2.6 0.2 ISIS 588540 5-10-5 MOE 44 0.7 2.5 0.2 ISIS 588838 3-10-3 cEt 45 0.7 3.1 0.2 ISIS 588842 Deoxy, MOE and cEt 41 0.6 2.6 0.2 ISIS 588843 3-10-3 cEt 43 0.7 2.9 0.2 ISIS 588844 Deoxy, MOE and cEt 43 0.7 2.8 0.2 ISIS 588851 Deoxy, MOE and cEt 46 0.6 2.6 0.2 ISIS 588854 Deoxy, MOE and cEt 45 0.7 4.1 0.2 ISIS 588855 Deoxy, MOE and cEt 44 0.7 2.9 0.3 ISIS 588856 Deoxy, MOE and cEt 44 0.7 3.2 0.2 ISIS 588865 Deoxy, MOE and cEt 45 0.7 2.6 0.3 ISIS 588867 Deoxy, MOE and cEt 46 0.7 3.2 0.3 ISIS 588868 Deoxy, MOE and cEt 42 0.7 2.9 0.3 ISIS 588870 Deoxy, MOE and cEt 43 0.6 2.2 0.2 ISIS 588871 Deoxy, MOE and cEt 41 0.7 3.1 0.2 ISIS 588872 Deoxy, MOE and cEt 39 0.6 3.2 0.3
Study 6 (with Deoxy, MOE and cEt Oligonucleotides)

[0485] Groups of eight- to nine-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 50 mg/kg of deoxy, MOE, and cEt oligonucleotides. Two groups of male CD1 mice were injected subcutaneously once a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0486] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, creatinine, bilirubin, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00049 TABLE 48 Plasma chemistry markers in CD1 mice plasma on day 45 ALT AST Albumin Creatinine Bilirubin BUN (IU/L) (IU/L) (g/dL) (mg/dL) (mg/dL) (mg/dL) PBS 39 78 3.4 0.2 0.2 31 PBS 37 59 2.9 0.1 0.2 27 ISIS 599552 167 208 3.0 0.1 0.2 32 ISIS 599553 43 86 2.9 0.1 0.2 28 ISIS 599554 57 101 2.2 0.2 0.2 31 ISIS 599569 469 530 3.5 0.2 0.3 27 ISIS 599577 37 84 2.9 0.1 0.1 31 ISIS 599578 45 104 2.8 0.1 0.2 30 ISIS 599581 54 88 3.1 0.1 0.2 31 ISIS 599590 1741 1466 3.1 0.1 0.3 25 ISIS 599591 2230 1183 3.2 0.1 0.3 27 ISIS 601209 68 104 2.9 0.1 0.2 30 ISIS 601212 1795 968 3.2 0.1 0.3 22 ISIS 601215 424 385 3.1 0.1 0.4 25 ISIS 601216 90 125 2.9 0.1 0.2 29 ISIS 601276 946 366 2.9 0.1 0.5 31 ISIS 601282 831 540 3.3 0.2 0.2 32

Weights

[0487] Body weights of the mice were measured on day 40. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 45. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00050 TABLE 49 Weights (g) of CD1 mice Body Kidney Liver Spleen PBS 40 0.7 2.1 0.2 PBS 42 0.8 2.3 0.2 ISIS 599552 38 0.6 2.3 0.2 ISIS 599553 39 0.7 2.2 0.2 ISIS 599554 39 0.7 2.4 0.2 ISIS 599569 39 0.7 2.2 0.2 ISIS 599577 41 0.7 2.5 0.2 ISIS 599578 37 0.6 2.0 0.2 ISIS 599581 40 0.6 2.5 0.2 ISIS 599590 34 0.6 3.5 0.2 ISIS 599591 38 0.8 2.7 0.2 ISIS 601209 42 0.7 2.6 0.3 ISIS 601212 38 0.6 2.9 0.2 ISIS 601215 36 0.7 2.6 0.2 ISIS 601216 42 0.6 2.7 0.2 ISIS 601276 42 0.7 3.2 0.2 ISIS 601282 38 0.7 3.2 0.2
Study 7 (with MOE Gapmers and Deoxy, MOE and cEt Oligonucleotides)

[0488] Groups of eight- to nine-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 100 mg/kg of ISIS oligonucleotides. One group of male CD1 mice was injected subcutaneously once a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0489] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00051 TABLE 50 Plasma chemistry markers in CD1 mice plasma on day 45 ALT AST Albumin Creatinine BUN Chemistry (IU/L) (IU/L) (g/dL) (mg/dL) (mg/dL) PBS 120 102 2.7 0.2 26 ISIS 588842 Deoxy, MOE and cEt 177 164 2.7 0.1 23 ISIS 588843 Deoxy, MOE and cEt 98 194 2.7 0.1 24 ISIS 588851 Deoxy, MOE and cEt 91 142 2.6 0.1 23 ISIS 588856 Deoxy, MOE and cEt 78 110 2.7 0.1 23 ISIS 599024 3-10-4 MOE 91 108 2.7 0.1 23 ISIS 599087 5-7-5 MOE 198 183 2.6 0.2 28 ISIS 599093 5-7-5 MOE 3285 2518 2.6 0.2 24 ISIS 599149 4-8-5 MOE 30 64 2.9 0.2 25 ISIS 599155 4-8-5 MOE 145 189 2.6 0.2 25 ISIS 599202 5-8-5 MOE 150 128 2.8 0.2 23 ISIS 599203 5-8-5 MOE 111 127 2.8 0.2 24 ISIS 599208 5-8-5 MOE 146 178 2.9 0.2 22 ISIS 599261 3-10-5 MOE 144 165 2.8 0.2 26 ISIS 599267 3-10-5 MOE 96 132 2.6 0.2 27 ISIS 599268 3-10-5 MOE 87 115 2.6 0.1 23 ISIS 599322 6-7-6 MOE 115 138 2.7 0.1 22 ISIS 599374 5-9-5 MOE 375 271 2.6 0.1 21 ISIS 599378 5-9-5 MOE 77 99 2.7 0.1 23 ISIS 599441 6-8-6 MOE 150 250 2.9 0.1 23

Weights

[0490] Body weights of the mice were measured on day 44. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 49. The results are presented in the Table below. ISIS oligonucleotides that caused changes in the weights outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00052 TABLE 51 Weights (g) of CD1 mice Chemistry Body Kidney Liver Spleen PBS 39 0.6 1.9 0.1 ISIS 588842 Deoxy, MOE and cEt 38 0.5 2.1 0.1 ISIS 588843 Deoxy, MOE and cEt 41 0.6 2.4 0.2 ISIS 588851 Deoxy, MOE and cEt 42 0.6 2.2 0.2 ISIS 588856 Deoxy, MOE and cEt 42 0.7 2.6 0.2 ISIS 599024 3-10-4 MOE 41 0.6 4.0 0.2 ISIS 599087 5-7-5 MOE 44 0.8 2.6 0.3 ISIS 599093 5-7-5 MOE 39 0.6 2.3 0.2 ISIS 599149 4-8-5 MOE 42 0.7 2.8 0.2 ISIS 599155 4-8-5 MOE 41 0.7 2.1 0.2 ISIS 599202 5-8-5 MOE 43 0.6 2.6 0.2 ISIS 599203 5-8-5 MOE 42 0.6 2.6 0.2 ISIS 599208 5-8-5 MOE 40 0.6 2.1 0.2 ISIS 599261 3-10-5 MOE 39 0.7 3.4 0.3 ISIS 599267 3-10-5 MOE 42 0.8 2.5 0.3 ISIS 599268 3-10-5 MOE 41 0.7 2.1 0.2 ISIS 599322 6-7-6 MOE 43 0.6 2.2 0.2 ISIS 599374 5-9-5 MOE 37 0.6 2.2 0.2 ISIS 599378 5-9-5 MOE 43 0.7 2.7 0.2 ISIS 599441 6-8-6 MOE 42 0.6 2.5 0.3
Study 8 (with MOE Gapmers, Deoxy, MOE and cEt Oligonucleotides, and cEt Gapmers)

[0491] Groups of eight- to nine-week old male CD1 mice were injected subcutaneously once a week for 6 weeks with 100 mg/kg of MOE gapmers, or 50 mg/kg of deoxy, MOE and cEt oligonucleotides or cEt gapmers. One group of male CD1 mice was injected subcutaneously once a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0492] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, albumin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). The results are presented in the Table below.

TABLE-US-00053 TABLE 52 Plasma chemistry markers in CD1 mice plasma on day 43 Dose ALT AST Albumin Creatinine BUN Chemistry (mg/kg/wk) (IU/L) (IU/L) (g/dL) (mg/dL) (mg/dL) PBS 37 57 2.5 0.08 26 ISIS 532770 5-10-5 MOE 100 57 73 2.5 0.07 24 ISIS 532800 5-10-5 MOE 100 74 126 2.8 0.10 26 ISIS 532809 5-10-5 MOE 100 83 73 2.5 0.07 23 ISIS 588540 5-10-5 MOE 100 106 102 2.7 0.09 27 ISIS 588544 5-10-5 MOE 100 66 62 2.6 0.10 24 ISIS 588548 5-10-5 MOE 100 48 67 2.6 0.08 23 ISIS 588550 5-10-5 MOE 100 65 106 2.5 0.10 25 ISIS 588553 5-10-5 MOE 100 78 90 2.6 0.09 25 ISIS 588555 5-10-5 MOE 100 94 89 2.5 0.08 23 ISIS 588848 Deoxy, MOE 50 38 54 2.3 0.07 25 and cEt ISIS 594430 3-10-3 cEt 50 63 72 2.5 0.10 27

Weights

[0493] Body weights of the mice were measured on day 36. Weights of organs, liver, kidney, and spleen were also measured after the mice were sacrificed on day 43. The results for the organ weights were expressed as a ratio to the body weights and normalized to the PBS control ratio.

TABLE-US-00054 TABLE 53 Organ Weights/Body weight (BW) of CD1 mice Dose Kidney/ Liver/ Spleen/ Chemistry (mg/kg/wk) BW BW BW PBS 1.0 1.0 1.0 ISIS 532770 5-10-5 MOE 100 1.4 1.1 1.0 ISIS 532800 5-10-5 MOE 100 1.5 1.1 0.9 ISIS 532809 5-10-5 MOE 100 1.3 1.2 0.9 ISIS 588540 5-10-5 MOE 100 1.3 1.2 1.0 ISIS 588544 5-10-5 MOE 100 1.6 1.1 1.0 ISIS 588548 5-10-5 MOE 100 1.7 1.2 1.0 ISIS 588550 5-10-5 MOE 100 1.5 1.2 1.0 ISIS 588553 5-10-5 MOE 100 1.5 1.0 0.8 ISIS 588555 5-10-5 MOE 100 1.8 1.2 1.0 ISIS 588848 Deoxy, MOE 50 1.3 1.0 0.9 and cEt ISIS 594430 3-10-3 cEt 50 1.4 1.1 0.9

Cytokine Assays

[0494] Blood obtained from all mice groups were sent to Antech Diagnostics for measurements of the various cytokine levels, such as IL-6, MDC, MIP1?, IP-10, MCP1, MIP-1?, and RANTES. The results are presented in Table 54.

TABLE-US-00055 TABLE 54 Cytokine levels (pg/mL) in CD1 mice plasma Chemistry IL-6 MDC MIP1? IP-10 MCP1 MIP-1? RANTES PBS 70 16 23 20 17 6 2 ISIS 532770 5-10-5 MOE 101 18 146 116 101 24 6 ISIS 532800 5-10-5 MOE 78 17 83 53 105 1 3 ISIS 532809 5-10-5 MOE 66 19 60 32 55 20 4 ISIS 588540 5-10-5 MOE 51 18 126 70 75 4 3 ISIS 588544 5-10-5 MOE 157 14 94 34 102 1 3 ISIS 588548 5-10-5 MOE 164 12 90 66 84 10 4 ISIS 588550 5-10-5 MOE 58 21 222 124 157 3 5 ISIS 588553 5-10-5 MOE 62 14 183 60 103 9 4 ISIS 588555 5-10-5 MOE 70 19 172 171 178 16 9 ISIS 588848 Deoxy, MOE 59 13 61 27 63 12 4 and cEt ISIS 594430 3-10-3 cEt 48 14 56 38 85 10 3
Hematology Assays Blood obtained from all mice groups were sent to Antech Diagnostics for measurements of hematocrit (HCT), as well as of the various blood cells, such as WBC, RBC, and platelets, and total hemoglobin (Hb) content. The results are presented in Table 55.

TABLE-US-00056 TABLE 55 Hematology markers in CD1 mice plasma HCT Hb WBC RBC Platelets Chemistry (%) (g/dL) (10.sup.3/?L) (10.sup.6/?L) (10.sup.3/?L) PBS 46 15 7 9 960 ISIS 532770 5-10-5 MOE 45 14 5 9 879 ISIS 532800 5-10-5 MOE 45 14 5 9 690 ISIS 532809 5-10-5 MOE 46 14 6 9 1005 ISIS 588540 5-10-5 MOE 49 15 6 10 790 ISIS 588544 5-10-5 MOE 36 11 7 7 899 ISIS 588548 5-10-5 MOE 46 14 6 9 883 ISIS 588550 5-10-5 MOE 42 13 8 8 721 ISIS 588553 5-10-5 MOE 45 14 6 9 719 ISIS 588555 5-10-5 MOE 43 13 8 9 838 ISIS 588848 Deoxy, MOE 40 15 8 10 840 and cEt ISIS 594430 3-10-3 cEt 45 14 8 9 993

Example 13: Tolerability of Antisense Oligonucleotides Targeting Human CFB in Sprague-Dawley Rats

[0495] Sprague-Dawley rats are a multipurpose model used for safety and efficacy evaluations. The rats were treated with ISIS antisense oligonucleotides from the studies described in the Examples above and evaluated for changes in the levels of various plasma chemistry markers.

Study 1 (with 5-10-5 MOE Gapmers)

[0496] Male Sprague-Dawley rats, seven- to eight-week old, were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously once a week for 6 weeks with 100 mg/kg of 5-10-5 MOE gapmers. One control group of 6 rats was injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis.

Liver Function

[0497] To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00057 TABLE 56 Liver function markers in Sprague-Dawley rats ALT AST (IU/L) (IU/L) PBS 66 134 ISIS 588544 101 329 ISIS 588550 69 157 ISIS 588553 88 304 ISIS 588554 202 243 ISIS 588555 94 113 ISIS 588556 102 117 ISIS 588560 206 317 ISIS 588564 292 594

Kidney Function

[0498] To evaluate the effect of ISIS oligonucleotides on kidney function, plasma levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Results are presented in the Table below, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00058 TABLE 57 Kidney function markers (mg/dL) in Sprague-Dawley rats BUN Creatinine PBS 18 3.5 ISIS 588544 21 3.1 ISIS 588550 21 3.0 ISIS 588553 22 2.8 ISIS 588554 23 3.0 ISIS 588555 22 3.5 ISIS 588556 21 3.2 ISIS 588560 26 2.4 ISIS 588564 24 2.7

Weights

[0499] Body weight measurements were taken on day 39. Liver, heart, spleen and kidney weights were measured at the end of the study on day 42, and are presented in the Table below. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00059 TABLE 58 Weights (g) Body Liver Spleen Kidney PBS 422 16 1.2 3.9 ISIS 588544 353 15 1.7 2.9 ISIS 588550 321 14 2.1 3.2 ISIS 588553 313 15 2.3 3.2 ISIS 588554 265 11 1.6 2.7 ISIS 588555 345 14 1.4 3.3 ISIS 588556 328 13 1.7 3.1 ISIS 588560 270 13 2.4 3.0 ISIS 588564 253 12 2.9 3.0
Study 2 (with Deoxy, MOE and cEt Oligonucleotides)

[0500] Male Sprague-Dawley rats, nine- to ten-week old, were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously once a week for 6 weeks with 100 mg/kg of deoxy, MOE, and cEt oligonucleotides. Two control groups of 3 rats each were injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis.

Liver Function

[0501] To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured on day 42 using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase), and albumin were measured and the results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00060 TABLE 59 Liver function markers in Sprague-Dawley rats ALT AST Albumin (IU/L) (IU/L) (g/dL) PBS 55 150 3.4 PBS 64 91 3.5 ISIS 588554 52 92 3.2 ISIS 588835 971 844 4.1 ISIS 588842 317 359 3.8 ISIS 588843 327 753 2.9 ISIS 588846 70 111 3.2 ISIS 588847 65 100 3.0 ISIS 588864 91 109 3.0 ISIS 594430 85 106 3.7

Kidney Function

[0502] To evaluate the effect of ISIS oligonucleotides on kidney function, plasma levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Results are presented in the Table below, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00061 TABLE 60 Kidney function markers (mg/dL) in Sprague-Dawley rats BUN Creatinine PBS 17 0.4 PBS 21 0.4 ISIS 588554 20 0.4 ISIS 588835 23 0.5 ISIS 588842 22 0.4 ISIS 588843 51 0.4 ISIS 588846 25 0.5 ISIS 588847 23 0.5 ISIS 588864 23 0.4 ISIS 594430 22 0.5

Weights

[0503] Body weight measurements were taken on day 39. Liver, heart, spleen and kidney weights were measured at the end of the study on day 42, and are presented in the Table below. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00062 TABLE 61 Weights (g) Body Liver Spleen Kidney PBS 466 16 0.9 3.8 PBS 485 16 0.9 3.6 ISIS 588554 393 15 2.3 2.6 ISIS 588835 387 16 1.0 3.3 ISIS 588842 414 22 1.5 3.7 ISIS 588843 427 20 2.5 4.2 ISIS 588846 366 16 2.1 3.3 ISIS 588847 402 15 1.6 3.1 ISIS 588864 364 15 2.1 3.8 ISIS 594430 420 16 1.2 3.6
Study 3 (with MOE Gapmers)

[0504] Male Sprague-Dawley rats, nine- to ten-week old, were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously once a week for 6 weeks with 100 mg/kg of MOE gapmers. One control group of 6 rats was injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis.

Liver Function

[0505] To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured on day 43 using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00063 TABLE 62 Liver function markers in Sprague-Dawley rats ALT AST Albumin Chemistry (IU/L) (IU/L) (g/dL) PBS 52 110 3.7 ISIS 588563 5-10-5 MOE 175 291 2.9 ISIS 599024 3-10-4 MOE 139 173 1.4 ISIS 599093 5-7-5 MOE 116 238 2.6 ISIS 599149 4-8-5 MOE 232 190 3.4 ISIS 599155 4-8-5 MOE 108 215 2.5 ISIS 599202 5-8-5 MOE 65 86 3.5 ISIS 599203 5-8-5 MOE 71 97 3.1 ISIS 599208 5-8-5 MOE 257 467 1.9 ISIS 599261 3-10-5 MOE 387 475 1.5 ISIS 599267 3-10-5 MOE 201 337 2.7

Kidney Function

[0506] To evaluate the effect of ISIS oligonucleotides on kidney function, plasma levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Results are presented in the Table below, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00064 TABLE 63 Kidney function markers (mg/dL) in Sprague-Dawley rats Chemistry BUN Creatinine PBS 16 0.3 ISIS 588563 5-10-5 MOE 26 0.4 ISIS 599024 3-10-4 MOE 135 1.2 ISIS 599093 5-7-5 MOE 29 0.4 ISIS 599149 4-8-5 MOE 23 0.4 ISIS 599155 4-8-5 MOE 29 0.4 ISIS 599202 5-8-5 MOE 19 0.4 ISIS 599203 5-8-5 MOE 22 0.4 ISIS 599208 5-8-5 MOE 26 0.3 ISIS 599261 3-10-5 MOE 228 1.6 ISIS 599267 3-10-5 MOE 24 0.4

Weights

[0507] Body weight measurements were taken on day 39. Liver, heart, spleen and kidney weights were measured at the end of the study on day 42, and are presented in the Table below. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00065 TABLE 64 Weights (g) Chemistry Body Liver Spleen Kidney PBS 471 16 1.0 4.1 ISIS 588563 5-10-5 MOE 311 16 3.4 4.1 ISIS 599024 3-10-4 MOE 297 11 1.0 3.5 ISIS 599093 5-7-5 MOE 332 18 4.1 5.0 ISIS 599149 4-8-5 MOE 388 16 2.3 3.7 ISIS 599155 4-8-5 MOE 290 15 2.9 4.5 ISIS 599202 5-8-5 MOE 359 13 1.3 3.2 ISIS 599203 5-8-5 MOE 334 14 1.8 3.3 ISIS 599208 5-8-5 MOE 353 29 4.7 4.6 ISIS 599261 3-10-5 MOE 277 10 0.9 3.2 ISIS 599267 3-10-5 MOE 344 21 3.9 4.7
Study 4 (with MOE Gapmers)

[0508] Male Sprague-Dawley rats, nine- to ten-week old, were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously once a week for 6 weeks with 100 mg/kg of MOE gapmers. One control group of 6 rats was injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis.

Liver Function

[0509] To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured on day 42 using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00066 TABLE 65 Liver function markers in Sprague-Dawley rats ALT AST Albumin Chemistry (IU/L) (IU/L) (g/dL) PBS 48 77 3.9 ISIS 532800 5-10-5 MOE 72 111 3.4 ISIS 532809 5-10-5 MOE 59 89 3.8 ISIS 588540 5-10-5 MOE 146 259 3.8 ISIS 599268 3-10-5 MOE 175 206 2.7 ISIS 599322 6-7-6 MOE 523 567 3.3 ISIS 599374 5-9-5 MOE 114 176 3.0 ISIS 599378 5-9-5 MOE 124 116 3.2 ISIS 599380 5-9-5 MOE 148 210 3.4 ISIS 599441 6-8-6 MOE 51 91 2.6

Kidney Function

[0510] To evaluate the effect of ISIS oligonucleotides on kidney function, plasma levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Results are presented in the Table below, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00067 TABLE 66 Kidney function markers (mg/dL) in Sprague-Dawley rats Chemistry BUN Creatinine PBS 15 0.4 ISIS 532800 5-10-5 MOE 26 0.5 ISIS 532809 5-10-5 MOE 18 0.5 ISIS 588540 5-10-5 MOE 22 0.5 ISIS 599268 3-10-5 MOE 28 0.5 ISIS 599322 6-7-6 MOE 24 0.5 ISIS 599374 5-9-5 MOE 29 0.5 ISIS 599378 5-9-5 MOE 22 0.4 ISIS 599380 5-9-5 MOE 26 0.5 ISIS 599441 6-8-6 MOE 24 0.4

Weights

[0511] Body weight measurements were taken on day 39. Liver, heart, spleen and kidney weights were measured at the end of the study on day 42, and are presented in the Table below. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00068 TABLE 67 Weights (g) Chemistry Body Liver Spleen Kidney PBS 502 16 0.9 3.7 ISIS 532800 5-10-5 MOE 376 16 2.0 3.4 ISIS 532809 5-10-5 MOE 430 16 1.4 3.4 ISIS 588540 5-10-5 MOE 391 16 1.8 3.5 ISIS 599268 3-10-5 MOE 332 16 3.6 3.6 ISIS 599322 6-7-6 MOE 348 13 2.1 3.4 ISIS 599374 5-9-5 MOE 302 12 2.0 3.3 ISIS 599378 5-9-5 MOE 332 11 1.1 2.8 ISIS 599380 5-9-5 MOE 350 11 1.5 3.3 ISIS 599441 6-8-6 MOE 368 16 2.5 3.3
Study 5 (with MOE Gapmers and Deoxy, MOE and cEt Oligonucleotides)

[0512] Male Sprague-Dawley rats, nine- to ten-week old, were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously once a week for 6 weeks with 100 mg/kg of MOE gapmer or with 50 mg/kg of deoxy, MOE and cEt oligonucleotides. One control group of 4 rats was injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis.

Liver Function

[0513] To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured on day 42 using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00069 TABLE 68 Liver function markers in Sprague-Dawley rats ALT AST Albumin Chemistry (IU/L) (IU/L) (g/dL) PBS 49 74 3.3 ISIS 532770 5-10-5 MOE 95 132 3.3 ISIS 588851 Deoxy, MOE, and cEt 47 72 3.1 ISIS 588856 Deoxy, MOE, and cEt 56 75 3.0 ISIS 588865 Deoxy, MOE, and cEt 62 84 2.9 ISIS 588867 Deoxy, MOE, and cEt 73 214 2.9 ISIS 588868 Deoxy, MOE, and cEt 59 83 3.1 ISIS 588870 Deoxy, MOE, and cEt 144 144 3.4

Kidney Function

[0514] To evaluate the effect of ISIS oligonucleotides on kidney function, plasma and urine levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Results are presented in the Tables below, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00070 TABLE 69 Kidney function markers (mg/dL) in the plasma of Sprague-Dawley rats Chemistry BUN Creatinine PBS 18 0.3 ISIS 532770 5-10-5 MOE 20 0.4 ISIS 588851 Deoxy, MOE, and cEt 20 0.4 ISIS 588856 Deoxy, MOE, and cEt 22 0.4 ISIS 588865 Deoxy, MOE, and cEt 24 0.5 ISIS 588867 Deoxy, MOE, and cEt 22 0.4 ISIS 588868 Deoxy, MOE, and cEt 19 0.4 ISIS 588870 Deoxy, MOE, and cEt 20 0.5

TABLE-US-00071 TABLE 70 Kidney function markers (mg/dL) in the urine of Sprague-Dawley rats Total Chemistry protein Creatinine PBS 80 92 ISIS 532770 5-10-5 MOE 466 69 ISIS 588851 Deoxy, MOE, and cEt 273 64 ISIS 588856 Deoxy, MOE, and cEt 259 68 ISIS 588865 Deoxy, MOE, and cEt 277 67 ISIS 588867 Deoxy, MOE, and cEt 337 68 ISIS 588868 Deoxy, MOE, and cEt 326 75 ISIS 588870 Deoxy, MOE, and cEt 388 82

Weights

[0515] Body weight measurements were taken on day 39. Liver, heart, spleen and kidney weights were measured at the end of the study on day 42, and are presented in the Table below. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00072 TABLE 71 Weights (g) Chemistry Body Liver Spleen Kidney PBS 489 16 0.9 3.5 ISIS 532770 5-10-5 MOE 372 15 1.7 3.1 ISIS 588851 Deoxy, MOE, and cEt 285 14 1.4 3.2 ISIS 588856 Deoxy, MOE, and cEt 415 15 1.1 3.3 ISIS 588865 Deoxy, MOE, and cEt 362 14 2.0 3.3 ISIS 588867 Deoxy, MOE, and cEt 406 15 2.4 3.4 ISIS 588868 Deoxy, MOE, and cEt 399 15 1.5 3.4 ISIS 588870 Deoxy, MOE, and cEt 446 14 1.4 3.3
Study 6 (with MOE Gapmers, Deoxy, MOE and cEt Oligonucleotides, and cEt Gapmers)

[0516] Male rats were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 rats each were injected subcutaneously once a week for 6 weeks with 100 mg/kg of MOE gapmers or with 50 mg/kg of deoxy, MOE and cEt oligonucleotide or cEt gapmer. One control group of 4 rats was injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis.

Liver Function

[0517] To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured on day 42 using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L.

TABLE-US-00073 TABLE 72 Liver function markers Dose ALT AST Albumin Chemistry (mg/kg/wk) (IU/L) (IU/L) (g/dL) PBS 54 73 4.3 ISIS 532770 5-10-5 MOE 100 57 114 4.4 ISIS 532800 5-10-5 MOE 100 176 180 4.3 ISIS 532809 5-10-5 MOE 100 71 132 4.1 ISIS 588540 5-10-5 MOE 100 89 202 4.4 ISIS 588544 5-10-5 MOE 100 75 152 3.9 ISIS 588548 5-10-5 MOE 100 50 71 4.1 ISIS 588550 5-10-5 MOE 100 80 133 3.6 ISIS 588553 5-10-5 MOE 100 59 112 3.9 ISIS 588555 5-10-5 MOE 100 97 142 3.8 ISIS 588848 Deoxy, MOE 50 53 82 3.9 and cEt ISIS 594430 3-10-3 cEt 50 198 172 4.4

Kidney Function

[0518] To evaluate the effect of ISIS oligonucleotides on kidney function, urine levels of total protein and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, NY). Results are presented in the Table below. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00074 TABLE 73 Total protein/creatinine ratio in the urine of rats Dose P/C Chemistry (mg/kg/wk) ratio PBS 1.1 ISIS 532770 5-10-5 MOE 100 8.3 ISIS 532800 5-10-5 MOE 100 6.5 ISIS 532809 5-10-5 MOE 100 6.1 ISIS 588540 5-10-5 MOE 100 10.1 ISIS 588544 5-10-5 MOE 100 7.9 ISIS 588548 5-10-5 MOE 100 6.6 ISIS 588550 5-10-5 MOE 100 7.6 ISIS 588553 5-10-5 MOE 100 7.0 ISIS 588555 5-10-5 MOE 100 6.2 ISIS 588848 Deoxy, MOE and cEt 50 5.2 ISIS 594430 3-10-3 cEt 50 5.3

Weights

[0519] Body weight measurements were taken on day 39. Liver, heart, spleen and kidney weights were measured at the end of the study on day 42, and are presented in the Table below. The results for the organ weights were expressed as a ratio to the body weights and normalized to the PBS control ratio.

TABLE-US-00075 TABLE 74 Organ weights/Body weight (BW) ratios Dose Spleen/ Liver/ Kidney/ Chemistry (mg/kg/wk) BW BW BW PBS 1.0 1.0 1.0 ISIS 532770 5-10-5 MOE 100 2.0 1.2 1.0 ISIS 532800 5-10-5 MOE 100 2.8 1.3 1.0 ISIS 532809 5-10-5 MOE 100 2.2 1.1 1.0 ISIS 588540 5-10-5 MOE 100 2.2 1.4 1.0 ISIS 588544 5-10-5 MOE 100 2.5 1.3 1.1 ISIS 588548 5-10-5 MOE 100 2.1 1.3 1.1 ISIS 588550 5-10-5 MOE 100 3.9 1.4 1.1 ISIS 588553 5-10-5 MOE 100 4.1 1.4 1.4 ISIS 588555 5-10-5 MOE 100 1.8 1.3 1.0 ISIS 588848 Deoxy, MOE 50 3.1 1.3 1.1 and cEt ISIS 594430 3-10-3 cEt 50 1.7 1.0 1.1

Example 14: Efficacy of Antisense Oligonucleotides Against CFB mRNA in hCFB Transgenic Mice

[0520] Selected compounds were tested for efficacy in human CFB transgenic mice, founder line #6. The human CFB gene is located on chromosome 6: position 31913721-31919861. A Fosmid (ABC14-50933200C.sub.23) containing the CFB sequence was selected to make transgenic mice expressing the human CFB gene. Cla I (31926612) and Age I (31926815) restriction enzymes were used to generate a 22,127 bp fragment containing the CFB gene for pronuclear injection. DNA was confirmed by restriction enzyme analysis using Pvu I. The 22,127 bp DNA fragment was injected into C.sub.57BL/6NTac embryos. 6 positive founders were bred. Founder #6 expressed the liver human CFB mRNA and was crossbreed to the 3.sup.rd generation. Progeny from 3rd generation mice were used to evaluate human CFB ASOs for human CFB mRNA reduction.

Treatment

[0521] Groups of 3 mice each were injected subcutaneously twice a week for the first week with 50 mg/kg of ISIS oligonucleotides, followed by once a week dosing with 50 mg/kg of ISIS oligonucleotides for an additional three weeks. One control group of 4 mice was injected subcutaneously twice a week for 2 weeks for the first week with PBS for the first week for an additional three weeks. Forty eight hours after the last dose, mice were euthanized and organs and plasma were harvested for further analysis.

RNA Analysis

[0522] At the end of the dosing period, RNA was extracted from the liver and kidney for real-time PCR analysis of CFB mRNA levels. Human CFB mRNA levels were measured using the human primer probe set RTS3459. CFB mRNA levels were normalized to RIBOGREEN?, and also to the housekeeping gene, Cyclophilin. Results were calculated as percent inhibition of CFB mRNA expression compared to the control.

[0523] All the antisense oligonucleotides effected inhibition of human CFB mRNA levels in the liver.

TABLE-US-00076 TABLE 75 Percent reduction of CFB mRNA levels in hCFB mice Normalized Normalized to to ISIS No RIBOGREEN Cyclophilin 532770 86 87 532800 88 87 532809 69 69 588540 95 94 588544 91 91 588548 78 77 588550 89 88 588553 94 94 588555 94 94 588848 83 82 594430 78 76

Example 15: In Vivo Antisense Inhibition of Murine CFB

[0524] Several antisense oligonucleotides were designed that were targeted to murine CFB mRNA (GENBANK Accession No. NM_008198.2, incorporated herein as SEQ ID NO: 5). The target start sites and sequences of each oligonucleotide are described in the table below. The chimeric antisense oligonucleotides in the table below were designed as 5-10-5 MOE gapmers. The gapmers are 20 nucleosides in length, wherein the central gap segment is comprised of 10 2-deoxynucleosides and is flanked on both sides (in the 5 and 3 directions) by wings comprising 5 nucleosides each. Each nucleoside in the 5 wing segment and each nucleoside in the 3 wing segment has a 2-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P?S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

TABLE-US-00077 TABLE76 GapmerstargetingmurineCFB TargetStart SEQ SiteonSEQ ID ISISNo Sequence IDNO:5 NO 516269 GCATAAGAGGGTACCAGCTG 2593 804 516272 GTCCTTTAGCCAGGGCAGCA 2642 805 516323 TCCACCCATGTTGTGCAAGC 1568 806 516330 CCACACCATGCCACAGAGAC 1826 807 516341 TTCCGAGTCAGGCTCTTCCC 2308 808

Treatment

[0525] Groups of four C.sub.57BL/6 mice each were injected with 50 mg/kg of ISIS 516269, ISIS 516272, ISIS 516323, ISIS 516330, or ISIS 516341 administered weekly for 3 weeks. A control group of mice was injected with phosphate buffered saline (PBS) administered weekly for 3 weeks.

CFB RNA Analysis

[0526] At the end of the study, RNA was extracted from liver tissue for real-time PCR analysis of CFB, using primer probe set RTS3430 (forward sequence GGGCAAACAGCAATTTGTGA, designated herein as SEQ ID NO: 816; reverse sequence TGGCTACCCACCTTCCTTGT, designated herein as SEQ ID NO: 817; probe sequence CTGGATACTGTCCCAATCCCGGTATTCCX, designated herein as SEQ ID NO: 818).

[0527] The mRNA levels were normalized using RIBOGREEN?. As shown in the Table below, some of the antisense oligonucleotides achieved reduction of murine CFB over the PBS control. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00078 TABLE 77 Percent inhibition of murine CFB mRNA in C57BL/6 mice ISIS No % 516269 29 516272 72 516323 77 516330 62 516341 72

Protein Analysis

[0528] CFB protein levels were measured in the kidney, liver, plasma, and in the eye by western Blot using goat anti-CFB antibody (Sigma Aldrich). Results are presented as percent inhibition of CFB, relative to PBS control. n/a indicates that measurements were not taken for that sample. As shown in the Table below, antisense inhibition of CFB by ISIS oligonucleotides resulted in a reduction of CFB protein in various tissues. As shown in the Table below, systemic administration of ISIS oligonucleotides was effective in reducing CFB levels in the eye.

TABLE-US-00079 TABLE 78 Percent inhibition of murine CFB protein in C57BL/6 mice ISIS No Kidney Liver Plasma Eye 516269 20 58 n/a 70 516272 48 74 n/a 99 516323 73 85 90 93 516330 77 80 n/a n/a 516341 80 88 68 n/a

Example 16: Dose-Dependent Antisense Inhibition of Murine CFB

[0529] Groups of four C.sub.57BL/6 mice each were injected with 25 mg/kg, 50 mg/kg, or 100 mg/kg of ISIS 516272, and ISIS 516323 administered weekly for 6 weeks. Another two groups of mice were injected with 100 mg/kg of ISIS 516330 or ISIS 516341 administered weekly for 6 weeks. Two control groups of mice were injected with phosphate buffered saline (PBS) administered weekly for 6 weeks.

CFB RNA Analysis

[0530] RNA was extracted from liver and kidney tissues for real-time PCR analysis of CFB, using primer probe set RTS3430. The mRNA levels were normalized using RIBOGREEN?. As shown in the Table below, the antisense oligonucleotides achieved dose-dependent reduction of murine CFB over the PBS control. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00080 TABLE 79 Percent inhibition of murine CFB mRNA in C57BL/6 mice Dose ISIS No (mg/kg/wk) Liver Kidney 516272 25 39 32 50 73 36 100 87 42 516323 25 36 41 50 65 47 100 79 71 516330 100 85 45 516341 200 89 65

Protein Analysis

[0531] CFB protein levels were measured in the plasma by western Blot using goat anti-CFB antibody (Sigma Aldrich). As shown in the table below, antisense inhibition of CFB by the ISIS oligonucleotides resulted in a reduction of CFB protein. Results are presented as percent inhibition of CFB, relative to PBS control. n/a indicates that measurements were not taken for that sample.

[0532] CFB protein levels were also measured in the eye by Western Blot. All treatment groups demonstrated an inhibition of CFB by 95%, with some sample measurements being below detection levels of the assay.

TABLE-US-00081 TABLE 80 Percent inhibition of murine CFB protein in C57BL/6 mice ISIS No Dose (mg/kg/wk) Liver 516272 25 32 50 70 100 83 516323 25 43 50 80 100 90 516330 100 n/a 516341 200 n/a

Example 17: Effect of Antisense Inhibition of CFB in the NZB/W F.SUB.1 .Mouse Model

[0533] The NZB/W F.sub.1 is the oldest classical model of lupus, where the mice develop severe lupus-like phenotypes comparable to that of lupus patients (Theofilopoulos, A. N. and Dixon, F. J. Advances in Immunology, vol. 37, pp. 269-390, 1985). These lupus-like phenotypes include lymphadenopathy, splenomegaly, elevated serum antinuclear autoantibodies (ANA) including anti-dsDNA IgG, a majority of which are IgG2a and IgG3, and immune complex-mediated glomerulonephritis (GN) that becomes apparent at 5-6 months of age, leading to kidney failure and death at 10-12 months of age.

Study 1

[0534] A study was conducted to demonstrate that treatment with antisense oligonucleotides targeting CFB would improve renal pathology in the mouse model. Female NZB/W F1 mice, 17 weeks old, were purchased from Jackson Laboratories. Groups of 16 mice each received doses of 100 ?g/kg/week of ISIS 516272 or ISIS 516323 for 20 weeks. Another group of 16 mice received doses of 100 ?g/kg/week of control oligonucleotide ISIS 141923 for 20 weeks. Another group of 10 mice received doses of PBS for 20 weeks and served as the control group to which all the other groups were compared. Terminal endpoints were collected 48 hours after the last dose was injected.

CFB RNA Analysis

[0535] RNA was extracted from liver and kidney tissue for real-time PCR analysis of CFB, using primer probe set RTS3430. The mRNA levels were normalized using RIBOGREEN?. As shown in the Table below, some of the antisense oligonucleotides achieved reduction of murine CFB over the PBS control. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00082 TABLE 81 Percent inhibition of murine CFB mRNA in NZB/W Fl mice ISIS No Liver Kidney 516272 55 25 516323 63 43 141923 0 0

Proteinuria

[0536] Proteinuria is expected in 60% of animals in this mouse model. The cumulative incidence of severe proteinuria was measured by calculating the total protein to creatinine ratio using a clinical analyzer. The results are presented in the table below and demonstrate that treatment with antisense oligonucleotides targeting CFB achieved reduction of proteinuria in the mice compared to the PBS control and the control oligonucleotide treated mice.

TABLE-US-00083 TABLE 82 Percent cumulative incidence of severe proteinuria in NZB/W F1 mice % PBS 40 ISIS 516272 6 ISIS 516323 0 ISIS 141923 25

Survival

[0537] Survival of the mice was monitored by keeping count of the mice at the start of treatment and then again at week 20. The results are presented in the table below and demonstrate that treatment with antisense oligonucleotides targeting CFB increased survival in the mice compared to the PBS control and the control oligonucleotide treated mice.

TABLE-US-00084 TABLE 83 Number of surviving mice and % survival Week Week % survival at 1 20 week 20 PBS 10 6 60 ISIS 516272 16 15 94 ISIS 516323 16 16 100 ISIS 141923 16 12 75

Glomerular Deposition

[0538] The amount of C.sub.3 deposition, as well as IgG deposition, in the glomeruli of the kidneys was measured by immunohistochemistry with an anti-C.sub.3 antibody. The results are presented in the table below and demonstrate that treatment with antisense oligonucleotides targeting CFB achieved reduction of both C.sub.3 and IgG depositions in the kidney glomeruli compared to the PBS control and the control oligonucleotide treated mice.

TABLE-US-00085 TABLE 84 Percent inhibition of glomerula deposition in NZB/W F1 mice ISIS No C3 IgG 516272 45 20 516323 48 2 141923 0 0

Study 2

[0539] Female NZB/W F1 mice, 16 weeks old, were purchased from Jackson Laboratories. A group of 10 mice received doses of 100 ?g/kg/week of ISIS 516323 for 12 weeks. Another group of 10 mice received doses of 100 ?g/kg/week of control oligonucleotide ISIS 141923 for 12 weeks. Another group of 10 mice received doses of PBS for 12 weeks and served as the control group to which all the other groups were compared. Terminal endpoints were collected 48 hours after the last dose was injected.

CFB RNA Analysis

[0540] RNA was extracted from liver and kidney tissue for real-time PCR analysis of CFB, using primer probe set RTS3430. As shown in the table below, treatment with ISIS 516323 achieved reduction of murine CFB over the PBS control. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00086 TABLE 85 Percent inhibition of murine CFB mRNA in NZB/W F1 mice ISIS No Liver Kidney 516323 75 46 141923 0 6

Proteinuria

[0541] The cumulative incidence of severe proteinuria was assessed by measuring urine total protein to creatinine ratio, as well as by measuring total microalbumin levels. The results are presented in the tables below and demonstrate that treatment with antisense oligonucleotides targeting CFB reduced proteinuria in the mice compared to the PBS control and the control oligonucleotide treated mice.

TABLE-US-00087 TABLE 86 Proteinuria in NZB/W F1 mice measured as urine microalbumin levels (mg/dl) ISIS No Week 0 Week 6 Week 8 Week 10 516323 0 0 5.4 0.4 141923 0 8.28 8.6 5.6

TABLE-US-00088 TABLE 87 Proteinuria in NZB/W F1 mice measured as total protein to creatinine ratio ISIS No Week 0 Week 6 Week 8 Week 10 516323 5.5 7.8 8.6 7.2 141923 6.9 10.0 13.5 7.2

Survival

[0542] Survival of the mice was monitored by keeping count of the mice at the start of treatment and then again at week 12. The results are presented in the table below and demonstrate that treatment with antisense oligonucleotides targeting CFB increased survival in the mice compared to the PBS control and the control oligonucleotide treated mice.

TABLE-US-00089 TABLE 88 Number of surviving mice Week 1 Week 12 PBS 10 9 ISIS 516323 10 10 ISIS 141923 10 9

Example 18: Effect of Antisense Inhibition of CFB in the MRL Mouse Model

[0543] The MRL/lpr lupus nephritis mouse model develops an SLE-like phenotype characterized by lymphadenopathy due to an accumulation of double negative (CD4.sup.? CD8.sup.?) and B220.sup.+ T-cells. These mice display an accelerated mortality rate. In addition, the mice have high concentrations of circulating immunoglobulins, which included elevated levels of autoantibodies such as ANA, anti-ssDNA, anti-dsDNA, anti-Sm, and rheumatoid factors, resulting in large amounts of immune complexes (Andrews, B. et al., J. Exp. Med. 148: 1198-1215, 1978).

Treatment

[0544] A study was conducted to investigate whether treatment with antisense oligonucleotides targeting CFB would reverse renal pathology in the mouse model. Female MRL/lpr mice, 14 weeks old, were purchased from Jackson Laboratories. A group of 10 mice received doses of 50 ?g/kg/week of ISIS 516323 for 7 weeks. Another group of 10 mice received doses of 50 ?g/kg/week of control oligonucleotide ISIS 141923 for 7 weeks. Another group of 10 mice received doses of PBS for 7 weeks and served as the control group to which all the other groups were compared. Terminal endpoints were collected 48 hours after the last dose was injected.

CFB RNA Analysis

[0545] RNA was extracted from liver tissue for real-time PCR analysis of CFB, using primer probe set RTS3430. As shown in the Table below, ISIS 516323 reduced CFB over the PBS control. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00090 TABLE 89 Percent inhibition of murine CFB mRNA in MRL/lpr mice ISIS No % 516323 68 141923 4

Renal Pathology

[0546] Renal pathology was evaluated by two methods. Histological sections of the kidney were stained with Haematoxylin & Eosin. The PBS control demonstrated presence of multiglomerular crescents tubular casts, which is a symptom of glomerulosclerosis. In contrast, the sections from mice treated with ISIS 516323 showed absent crescents tubular casts with minimal bowman capsule fibrotic changes, moderate to severe segmental mesangial cell expansion and glomerular basement membrane thickening.

[0547] Accumulation of C3 in the kidney was also assessed by immunohistochemistry with anti-C3 antibodies. The whole kidney C3 immunohistochemistry intensity score was calculated by intensity scoring system, which was computed by capturing 10 glomeruli per kidney and calculation the intensity of positive C3 staining. The results are presented in the table below and demonstrate that treatment with ISIS 516323 reduced renal C3 accumulation compared to the control groups.

TABLE-US-00091 TABLE 90 Renal C3 accumulation in MRL/lpr mice Whole C3 quantification kidney C3 (area/total area) % intensity score of average PBS PBS 2.5 100 ISIS 516323 1.6 68 ISIS 141923 2.2 99

Plasma C3 Levels

[0548] Reduction of CFB inhibits activation of the alternative complement pathway, preventing C.sub.3 consumption and leading to an apparent elevation of plasma C3 levels. Plasma C3 levels from terminal bleed were measured by clinical analyzer. The results are presented in the table below and demonstrate that treatment with ISIS 516323 increased C3 levels (p<0.001) in the plasma compared to the control groups.

TABLE-US-00092 TABLE 91 Plasma C3 levels (mg/dL) in MRL/lpr mice ISIS No C3 516323 28 141923 16

[0549] The results indicate that treatment with antisense oligonucleotides targeting CFB reverses renal pathology in the lupus mouse model.

Example 19: Effect of Antisense Inhibition of CFB in the CFH Het Mouse Model

[0550] CFH heterozygous (CFH Het, CFH.sup.+/?) mouse model expresses a mutant Factor H protein in combination with the full-length mouse protein (Pickering, M. C. et al., J. Exp. Med. 2007, 204: 1249-56). Renal histology remains normal in these mice up to six months old.

Study 1

[0551] Groups of 8 CFH.sup.+/? mice, 6 weeks old, each received doses of 75 mg/kg/week of ISIS 516323 or ISIS 516341 for 6 weeks. Another group of 8 mice received doses of 75 mg/kg/week of control oligonucleotide ISIS 141923 for 6 weeks. Another group of 8 mice received doses of PBS for 6 weeks and served as the control group to which all the other groups were compared. Terminal endpoints were collected 48 hours after the last dose was injected.

CFB RNA Analysis

[0552] RNA was extracted from liver and kidney tissue for real-time PCR analysis of CFB, using primer probe set RTS3430. As shown in the Table below, the antisense oligonucleotides reduced CFB over the PBS control. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00093 TABLE 92 Percent inhibition of murine CFB mRNA in CFH.sup.+/? mice ISIS No Liver Kidney 516323 80 38 516341 90 44 141923 0 17

[0553] Plasma C.sub.3 levels

[0554] Reduction of CFB inhibits activation of the alternative complement pathway, preventing C.sub.3 consumption and leading to an apparent elevation of plasma C.sub.3 levels. Plasma C.sub.3 levels from terminal plasma collection were measured by clinical analyzer. The results are presented in the table below and demonstrate that treatment with ISIS 516323 increased C.sub.3 to normal levels in the plasma.

TABLE-US-00094 TABLE 93 Plasma C3 levels (mg/dL) in CFH.sup.+/? mice ISIS No C3 516323 15 516341 17 141923 8

Study 2

[0555] Groups of 5 CFH.sup.+/? mice each received doses of 12.5 mg/kg/week, 25 mg/kg/week, 50 mg/kg/week, 75 mg/kg/week, or 100 mg/kg/week of ISIS 516323 or ISIS 516341 for 6 weeks. Another group of 5 mice received doses of 75 ?g/kg/week of control oligonucleotide ISIS 141923 for 6 weeks. Another group of 5 mice received doses of PBS for 6 weeks and served as the control group to which all the other groups were compared. Terminal endpoints were collected 48 hours after the last dose was injected.

CFB RNA Analysis

[0556] RNA was extracted from liver and kidney tissue for real-time PCR analysis of CFB, using primer probe set RTS3430. As shown in the Table below, the antisense oligonucleotides reduced CFB over the PBS control in a dose dependent manner. Results are presented as percent inhibition of CFB, relative to control.

TABLE-US-00095 TABLE 94 Percent inhibition of murine CFB mRNA in the liver of CFH.sup.+/? mice ISIS No Dose (mg/kg/week) % 516323 12.5 34 25 51 50 72 75 79 100 92 516341 12.5 38 25 57 50 89 75 92 100 90 141923 75 13
Plasma C.sub.3 levels

[0557] Reduction of CFB inhibits activation of the alternative complement pathway, preventing C.sub.3 consumption and leading to an apparent elevation of plasma C.sub.3 levels. Plasma C.sub.3 levels from terminal plasma collection were measured by clinical analyzer. The results are presented in the table below and demonstrate that treatment with ISIS oligonucleotides targeting CFB increased C.sub.3 levels in the plasma.

TABLE-US-00096 TABLE 95 Plasma C3 levels (mg/dL) in CFH.sup.+/? mice Dose (mg/kg/week) C3 PBS 10.1 516323 12.5 11.4 25 15.5 50 17.0 75 18.3 100 18.8 516341 12.5 12.1 25 16.3 50 18.6 75 22.1 100 19.1 141923 75 8.9

Example 20: Effect of ISIS Antisense Oligonucleotides Targeting Human CFB in Cynomolgus Monkeys

[0558] Cynomolgus monkeys were treated with ISIS antisense oligonucleotides selected from studies described in the Examples above. Antisense oligonucleotide efficacy and tolerability, as well as their pharmacokinetic profile in the liver and kidney, were evaluated.

[0559] At the time this study was undertaken, the cynomolgus monkey genomic sequence was not available in the National Center for Biotechnology Information (NCBI) database; therefore cross-reactivity with the cynomolgus monkey gene sequence could not be confirmed. Instead, the sequences of the ISIS antisense oligonucleotides used in the cynomolgus monkeys was compared to a rhesus monkey sequence for homology. The human antisense oligonucleotides tested below are cross-reactive (with 0 or 1 mismatches) with the rhesus genomic sequence (GENBANK Accession No. NW_001116486.1 truncated from nucleotides 536000 to 545000, designated herein as SEQ ID NO: 3). The start and stop sites of each oligonucleotide targeted to SEQ ID NO: 3 is presented in the Table below. Start site indicates the 5-most nucleotide to which the gapmer is targeted in the rhesus monkey gene sequence. Mismatches indicates the number of nucleobases in the human oligonucleotide that are mismatched with the rhesus genomic sequence.

TABLE-US-00097 TABLE 96 Antisense oligonucleotides complementary to the rhesus CFB genomic sequence (SEQ ID NO: 3) Target SEQ ISIS No Start Site Mismatches Chemistry ID NO 532770 6788 0 5-10-5 MOE 198 532800 7500 0 5-10-5 MOE 228 532809 7614 0 5-10-5 MOE 237 588540 7627 1 5-10-5 MOE 440 588544 7631 1 5-10-5 MOE 444 588548 7635 1 5-10-5 MOE 448 588550 7637 1 5-10-5 MOE 450 588553 7640 1 5-10-5 MOE 453 588555 7643 0 5-10-5 MOE 455 588848 7639 1 Deoxy, MOE and cEt 598 594430 6790 0 3-10-3 cEt 549

Treatment

[0560] Prior to the study, the monkeys were kept in quarantine for at least a 30 day period, during which the animals were observed daily for general health. The monkeys were 2-4 years old and weighed between 2 and 4 kg. Eleven groups of 4-6 randomly assigned male cynomolgus monkeys each were injected subcutaneously with ISIS oligonucleotide or PBS at four sites on the back in a clockwise rotation (i.e. left, top, right, and bottom), one site per dose. The monkeys were given four loading doses of PBS or 40 mg/kg of ISIS 532800, ISIS 532809, ISIS 588540, ISIS 588544, ISIS 588548, ISIS 588550, ISIS 588553, ISIS 588555, ISIS 588848, or ISIS 594430 for the first week (days 1, 3, 5, and 7), and were subsequently dosed once a week for 12 weeks (days 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84) with PBS or 40 mg/kg of ISIS oligonucleotide. ISIS 532770 was tested in a separate study with similar conditions with two male and two female cynomolgus monkeys in the group.

Hepatic Target Reduction

RNA Analysis

[0561] On day 86, liver and kidney samples were collected in duplicate (approximately 250 mg each) for CFB mRNA analysis. The samples were flash frozen in liquid nitrogen at necropsy within approximately 10 minutes of sacrifice.

[0562] RNA was extracted from liver and kidney for real-time PCR analysis of measurement of mRNA expression of CFB. Results are presented as percent change of mRNA, relative to PBS control, normalized with RIBOGREEN?. RNA levels were also normalized with the house-keeping gene, Cyclophilin A. RNA levels were measured with the primer probe sets RTS3459, described above, or RTS4445_MGB (forward sequence CGAAGAAGCTCAGTGAAATCAA, designated herein as SEQ ID NO: 819; reverse sequence TGCCTGGAGGGCCCTCTT, designated herein as SEQ ID NO: 820; probe sequence AGACCACAAGTTGAAGTC, designated herein as SEQ ID NO: 815).

[0563] As shown in the Tables below, treatment with ISIS antisense oligonucleotides resulted in reduction of CFB mRNA in comparison to the PBS control. Analysis of CFB mRNA levels revealed that several of the ISIS oligonucleotides reduced CFB levels in liver and/or kidney. Here 0 indicates that the expression levels were not inhibited. * indicates that the oligonucleotide was tested in a separate study with similar conditions.

TABLE-US-00098 TABLE 97 Percent inhibition of CFB mRNA in the cynomolgus monkey liver relative to the PBS control RTS3459/ RTS3459/ RTS445_MGB/ RTS445_MGB/ ISIS No Cyclophilin A RIBOGREEN Cyclophilin A RIBOGREEN 532770* 12 37 24 45 532800 54 45 56 46 588540 31 27 28 24 588548 68 67 68 67 588550 53 39 51 37 588553 74 59 74 59 588555 73 71 71 69 588848 9 0 6 0 594430 24 26 23 25

TABLE-US-00099 TABLE 98 Percent inhibition of CFB mRNA in the cynomolgus monkey kidney relative to the PBS control RTS3459/ RTS3459/ RTS445_MGB/ RTS445_MGB/ ISIS No Cyclophilin A RIBOGREEN Cyclophilin A RIBOGREEN 532770* 34 56 2 31 532800 36 30 43 37 588540 70 71 67 69 588548 83 84 82 83 588550 81 77 78 74 588553 86 84 86 85 588555 32 34 48 50 588848 89 91 87 90 594430 33 37 19 23

Protein Analysis

[0564] Approximately 1 mL of blood was collected from all available animals at day 85 and placed in tubes containing the potassium salt of EDTA. The blood samples were placed in wet-ice or Kryorack immediately, and centrifuged (3000 rpm for 10 min at 4? C.) to obtain plasma (approximately 0.4 mL) within 60 minutes of collection. Plasma levels of CFB were measured in the plasma by radial immunodiffusion (RID), using a polyclonal anti-Factor B antibody. The results are presented in the Table below. ISIS 532770 was tested in a separate study and plasma protein levels were measured on day 91 or 92 in that group.

[0565] Analysis of plasma CFB revealed that several ISIS oligonucleotides reduced protein levels in a sustained manner. ISIS 532770, which was tested in a separate study, reduced CFB protein levels on day 91/92 by 50% compared to baseline values. The reduction in plasma CFB protein levels correlates well with liver CFB mRNA level reduction in the corresponding groups of animals.

TABLE-US-00100 TABLE 99 Plasma protein levels (% baseline values) in the cynomolgus monkey Day 1 Day 30 Day 58 Day 72 Day 86 PBS 113 115 95 83 86 ISIS 532800 117 68 52 39 34 ISIS 532809 104 121 100 80 71 ISIS 588540 108 72 61 40 38 ISIS 588544 118 74 53 33 29 ISIS 588548 110 41 28 20 16 ISIS 588550 104 64 54 38 37 ISIS 588553 97 42 35 18 16 ISIS 588555 107 35 37 18 18 ISIS 588848 116 95 92 69 71 ISIS 594430 104 64 59 45 46

Tolerability Studies

Body Weight Measurements

[0566] To evaluate the effect of ISIS oligonucleotides on the overall health of the animals, body and organ weights were measured and are presented in the Table below. * indicates that the oligonucleotide was tested in a separate study with similar conditions and is the average of the measurements from male and female monkeys. The results indicate that effect of treatment with antisense oligonucleotides on body and organ weights was within the expected range for antisense oligonucleotides.

TABLE-US-00101 TABLE 100 Final body weights (g) in cynomolgus monkey Day Day Day Day Day Day Day 1 14 28 42 56 70 84 PBS 2887 2953 3028 3094 3125 3143 3193 ISIS 532770* 2963 2947 2966 3050 3097 3138 3160 ISIS 532800 2886 2976 3072 3149 3220 3269 3265 ISIS 532809 2755 2836 2927 2983 3019 3071 3098 ISIS 588540 2779 2834 2907 2934 2981 3034 3057 ISIS 588544 2837 2896 3009 3064 3132 3163 3199 ISIS 588548 2694 2816 2882 2990 3073 3149 3161 ISIS 588550 2855 2988 3062 3188 3219 3282 3323 ISIS 588553 3033 3156 3256 3335 3379 3372 3442 ISIS 588555 2757 2863 2965 3022 3075 3088 3158 ISIS 588848 2850 3018 3032 3187 3230 3212 3291 ISIS 594430 2884 2963 2953 3149 3187 3204 3256

TABLE-US-00102 TABLE 101 Final organ weights (g) in cynomolgus monkey Spleen Heart Kidney Liver PBS 2.8 11.6 11.9 55.8 ISIS 532770* 5.0 11.3 20.6 77.9 ISIS 532800 6.2 11.9 18.6 94.4 ISIS 588540 4.0 11.4 13.5 67.1 ISIS 588548 4.1 11.7 17.3 72.0 ISIS 588550 5.8 10.9 18.5 81.8 ISIS 588553 5.0 12.7 17.2 85.9 ISIS 588555 4.7 11.8 15.9 88.3 ISIS 588848 5.0 12.7 14.4 75.7 ISIS 594430 3.9 11.9 14.8 69.9

Liver Function

[0567] To evaluate the effect of ISIS oligonucleotides on hepatic function, blood samples were collected from all the study groups. The blood samples were collected from the cephalic, saphenous, or femoral veins, 48 hours post-dosing. The monkeys were fasted overnight prior to blood collection. Blood (1.5 mL) was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 minutes and then centrifuged (approximately 3,000 rpm for 10 min) to obtain serum. Levels of various liver function markers were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan).

[0568] Plasma levels of ALT and AST were measured and the results are presented in the Table below, expressed in IU/L. Bilirubin, a liver function marker, was similarly measured and is presented in the Table below expressed in mg/dL. * indicates that the oligonucleotide was tested in a separate study with similar conditions and is the average of the measurements from male and female monkeys. The results indicate that most of the antisense oligonucleotides had no effect on liver function outside the expected range for antisense oligonucleotides.

TABLE-US-00103 TABLE 102 Liver chemistry marker levels in cynomolgus monkey plasma on day 86 ALT (IU/L) AST (IU/L) Bilirubin (mg/dL) PBS 71 57 0.3 ISIS 532770* 59 58 0.1 ISIS 532800 65 86 0.1 ISIS 532809 35 58 0.1 ISIS 588540 70 88 0.2 ISIS 588544 55 97 0.2 ISIS 588548 61 85 0.2 ISIS 588550 94 84 0.2 ISIS 588553 44 65 0.2 ISIS 588555 63 84 0.2 ISIS 588848 69 65 0.2 ISIS 594430 86 53 0.2

Kidney Function

[0569] To evaluate the effect of ISIS oligonucleotides on kidney function, blood samples were collected from all the study groups. The blood samples were collected from the cephalic, saphenous, or femoral veins, 48 hours post-dosing. The monkeys were fasted overnight prior to blood collection. Blood was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 minutes and then centrifuged (approximately 3,000 rpm for 10 min) to obtain serum. Levels of BUN and creatinine were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). Results are presented in the Table below, expressed in mg/dL. * indicates that the oligonucleotide was tested in a separate study with similar conditions and is the average of the measurements from male and female monkeys.

[0570] For urinalysis, fresh urine from all the animals was collected in the morning using a clean cage pan on wet ice. Food was removed overnight the day before urine collection but water was supplied. Urine samples (approximately 1 mL) were analyzed for protein to creatinine (P/C) ratio using a Toshiba 200FR NEO automated chemistry analyzer (Toshiba Co., Japan). n.d. indicates that the urine protein level was under the detection limit of the analyzer.

[0571] The plasma and urine chemistry data indicate that most of the ISIS oligonucleotides did not have any effect on the kidney function outside the expected range for antisense oligonucleotides.

TABLE-US-00104 TABLE 103 Renal chemistry marker levels (mg/dL) in cynomolgus monkey plasma on day 86 BUN Creatinine Total protein PBS 28 0.9 8.0 ISIS 532770* 20 0.9 6.9 ISIS 532800 25 0.9 7.5 ISIS 532809 23 0.8 7.4 ISIS 588540 30 0.8 7.5 ISIS 588544 26 0.9 7.4 ISIS 588548 25 0.9 7.6 ISIS 588550 24 0.9 7.2 ISIS 588553 25 0.8 7.2 ISIS 588555 25 0.8 7.6 ISIS 588848 24 0.9 7.5 ISIS 594430 25 0.8 7.2

TABLE-US-00105 TABLE 104 Total Protein/Creatinine ratio in cynomolgus monkey urine Day 44 Day 86 PBS 0.03 n.d. ISIS 532800 0.01 n.d. ISIS 532809 0.01 n.d. ISIS 588540 0.03 n.d. ISIS 588544 0.01 0.09 ISIS 588548 0.01 0.01 ISIS 588550 0.04 0.01 ISIS 588553 0.05 n.d. ISIS 588555 0.03 0.03 ISIS 588848 0.09 n.d. ISIS 594430 0.03 n.d.

Hematology

[0572] To evaluate any effect of ISIS oligonucleotides in cynomolgus monkeys on hematologic parameters, blood samples of approximately 0.5 mL of blood was collected from each of the available study animals in tubes containing K.sub.2-EDTA. Samples were analyzed for red blood cell (RBC) count, white blood cells (WBC) count, individual white blood cell counts, such as that of monocytes, neutrophils, lymphocytes, as well as for platelet count, hemoglobin content and hematocrit, using an ADVIA120 hematology analyzer (Bayer, USA). The data is presented in the Tables below. * indicates that the oligonucleotide was tested in a separate study with similar conditions and is the average of the measurements from male and female monkeys.

[0573] The data indicate the oligonucleotides did not cause any changes in hematologic parameters outside the expected range for antisense oligonucleotides at this dose.

TABLE-US-00106 TABLE 105 Blood cell counts in cynomolgus monkeys RBC Platelets WBC Neutrophils Lymphocytes Monocytes (?10.sup.6/?L) (?10.sup.3/?L) (?10.sup.3/?L) (% WBC) (% total) (% total) PBS 5.8 347 9.4 42.7 53.1 3.0 ISIS 532770* 5.4 386 10.8 22.3 71.7 3.3 ISIS 532800 5.6 360 13.1 29.5 61.1 6.5 ISIS 532809 5.2 400 11.5 56.6 38.2 2.5 ISIS 588540 5.5 367 11.7 50.9 42.7 2.1 ISIS 588544 5.2 373 14.3 56.6 37.6 4.3 ISIS 588548 5.1 373 9.7 40.4 54.3 3.9 ISIS 588550 6.1 343 9.9 32.1 61.7 4.6 ISIS 588553 5.2 424 9.3 41.7 53.2 3.6 ISIS 588555 5.1 411 9.6 45.1 49.7 3.5 ISIS 588848 5.7 370 10.0 39.8 55.8 3.1 ISIS 594430 5.7 477 10.6 47.3 47.8 3.6

TABLE-US-00107 TABLE 106 Hematologic parameters in cynomolgus monkeys Hemoglobin HCT (g/dL) (%) PBS 14.1 46.6 ISIS 532770* 12.4 40.9 ISIS 532800 12.3 40.5 ISIS 532809 12.2 40.4 ISIS 588540 12.5 41.5 ISIS 588544 11.9 38.1 ISIS 588548 12.3 39.6 ISIS 588550 13.4 45.0 ISIS 588553 12.6 39.8 ISIS 588555 11.6 38.1 ISIS 588848 13.2 42.7 ISIS 594430 13.4 43.1

Measurement of Oligonucleotide Concentration

[0574] The concentration of the full-length oligonucleotide was measured in the kidney and liver tissues. The method used is a modification of previously published methods (Leeds et al., 1996; Geary et al., 1999) which consist of a phenol-chloroform (liquid-liquid) extraction followed by a solid phase extraction. Tissue sample concentrations were calculated using calibration curves, with a lower limit of quantitation (LLOQ) of approximately 1.14 ?g/g. The results are presented in the Table below, expressed as ?g/g liver or kidney tissue.

TABLE-US-00108 TABLE 107 Antisense oligonucleotide distribution Kidney (?g/g) Liver (?g/g) Kidney/Liver ratio ISIS 532800 3881 1633 2.4 ISIS 588540 3074 1410 2.2 ISIS 588548 3703 1233 3.0 ISIS 588550 4242 860 4.9 ISIS 588553 3096 736 4.2 ISIS 588555 4147 1860 2.2 ISIS 588848 2235 738 3.0 ISIS 594430 1548 752 2.1