Compositions and Methods for Treating Cancer

Abstract

A method of inhibiting skin cancer by administering to a subject in need thereof a double stranded RNA interference (RNAi) agent comprising at least one of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, and (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA and the use of the RNAi agent as a pharmaceutical composition for the treatment of cancer in subjects in need of treatment.

Claims

1. An isolated cell comprising a double stranded RNAi agent combination of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, and (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA wherein the antisense strand of (i) the first dsRNA is selected from SEQ ID NO:1-93 and the antisense strand of (ii) the second dsRNA is selected from SEQ ID NO: 187-560 wherein * is a phosphorothioate linkage.

2. A pharmaceutical composition for inhibiting expression of a CD320 gene and a LRP2 gene, the pharmaceutical composition comprising a combination of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, and (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA wherein the antisense strand of (i) the first dsRNA is selected from SEQ ID NO:1-93 and the antisense strand of (ii) the second dsRNA is selected from SEQ ID NO: 187-560 wherein * is a phosphorothioate linkage; and an excipient.

3. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of CD320 expression and an inhibitor of LRP2 expression in an amount effective to inhibit proliferation of the CC, wherein the inhibitor of CD320 expression is a first double-stranded ribonucleic acid (dsRNA) comprising a sense strand and an antisense strand forming a duplex, and the inhibitor of LRP2 expression is a second dsRNA comprising a sense strand and an antisense strand forming a duplex, wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA wherein the CC is from a skin cancer and wherein the antisense strand of (i) the first dsRNA is selected from SEQ ID NO:1-93 and the antisense strand of (ii) the second dsRNA is selected from SEQ ID NO: 187-560 wherein * is a phosphorothioate linkage.

4. The method of claim 3 wherein the contacting of the CC with an inhibitor of CD320 expression and an inhibitor of LRP2 expression is topical.

5. A method for treating skin cancer in a subject comprising administering to a subject an inhibitor of CD320 expression and an inhibitor of LRP2 expression in an amount effective to inhibit proliferation or kill cancer cells (CC) of the skin cancer wherein the CC is from the skin cancer and wherein the inhibitor is a combination of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, and (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA wherein the antisense strand of (i) the first dsRNA is selected from SEQ ID NO:1-93 and the antisense strand of (ii) the second dsRNA is selected from SEQ ID NO: 187-560 wherein * is a phosphorothioate linkage.

6. The method of claim 5 wherein the step of administering is topical administration to the skin cancer of the subject being treated.

7. A method for treating cancer in a subject who has recurring or relapsed cancer comprising administering to a subject an inhibitor of CD320 expression and an inhibitor of LRP2 expression in an amount effective to inhibit proliferation or kill cancer cells (CC) of the cancer wherein the CC is from a skin cancer and wherein the inhibitor is a combination of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, and (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA wherein the antisense strand of (i) the first dsRNA is selected from SEQ ID NO:1-93 and the antisense strand of (ii) the second dsRNA is selected from SEQ ID NO: 187-560 wherein * is a phosphorothioate linkage.

8. The method of claim 7 wherein the step of administering is topical administration to the skin cancer of the subject being treated.

Description

DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0036] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating one or more embodiments of the invention and are not to be construed as limiting the invention. In the drawings:

[0037] FIG. 1 illustrates an experimental design for knocking down CD320 and LRP2 in a cell. Cells were plated on day 0. The next day (day 1), virus particles encoding short hairpin RNAs (shRNAs) directed at the CD320 and LRP2 mRNA or a non-targeting shRNA control were added to the cell culture together with protamine sulfate, a reagent that facilitates cell entry of the virus particles. Table 1 shows the sequences that were used. Each shRNA coding sequence was also combined with a unique drug resistance gene, which would allow for selecting those cells that had taken up the shRNA; cells that had not taken up the shRNA would not survive. On day 2, drug selection was started. On day 3, the cells were harvested and plated in a new dish. Only the cells with a drug resistance gene, i.e., those cells that had taken up shRNA virus particles would survive this re-plating procedure. From day 4 on, each culture was closely observed for cell growth. Cells infected with the non-targeting negative control shRNA continued growing-data not shown. The results for the cell lines that expressed the CD320+LRP2 shRNAs are shown in Table 1.

[0038] FIGS. 2A-C illustrate sensitivity of cancer cell lines to knockdown of CD320 and LRP2. Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentiviruses expressing shRNAs to control sequences or to shCD320 and shLRP2 as described in FIG. 1. The cells were grown as described in FIG. 1. On the ninth day after transfection with the lentiviruses, pictures of the cells were taken. The solid oval indicates healthy growth of normal fibroblast infected with shRNAs to CD320 and LRP2. The broken line ovals indicate unhealthy dying cancer cells infected with shRNAs targeting CD320 and LRP2 (FIG. 2A). The fields of cells in FIG. 2A were counted and quantified and illustrated in FIG. 2B. The data in FIG. 2B were normalized to the number of control cells and illustrated in FIG. 2C. FIG. 2C. shows that the cultures of cells infected with lentivirus encoding the shRNAs against CD320 and LRP2 (white bars) contain far fewer cells than the cultures of cells exposed to the shRNA control (black bar).

[0039] FIGS. 3A-F illustrate graphs of protein levels resulting from transfection of HEK293, MDA-MB-435S and MDA-MB-231 cells with siRNA to LRP2 and CD320. HEK293, MDA-MB-435S and MDA-MB-231 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and OSC47. siRNAs targeting LRP2 are designated OSL245, OSL47, OSL104, OSL90 and OSL119. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIG. 3A-F represent the fold change of protein levels compared to siScramble (OSS1 or OSS2). (Average+/SEM is shown, n=3).

[0040] FIGS. 4A-F illustrate a graph of cells after transfection of LnCAP, MCF-7 and U251 cells with siRNA to LRP2 and CD320. LnCAP, MCF-7 and U251 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and OSC47. SiRNAs targeting LRP2 are designated OSL245, OSL47, OSL104, OSL90 and OSL119). Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIG. 4A-F represent the fold change of protein levels compared to siScramble (OSS2).

[0041] FIGS. 5A-C illustrate graphs of protein levels after transfection of A172, DU145 and GM05659 cells with siRNA to LRP2 and CD320. A172, DU145 and GM05659 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and OSC47. siRNAs targeting LRP2 are designated OSL245, OSL47, OSL104, OSL90 and OSL119). Whole cell lysates were prepared and immunoblotted for CD320. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIG. 5A-C represent the fold change of protein levels compared to siScramble (OSS2).

[0042] FIG. 6 illustrates a graph of relative LRP2 protein expression in various cell lines-Lysates were made from the cell lines indicated on the x-axis, and western blot was performed to determine LRP2 protein levels. The results represent the averages+/SEM of three independent lysates.

[0043] FIGS. 7A-B illustrates graphs of the effect of doxorubicin treatment on cell viability, as measured by the CTG assay. A172 and HCC15 cells were plated at 1200 cells/well in a 96 well plate. The next day, cells were treated with doxorubicin at the indicated concentrations. Four days after doxorubicin treatment was initiated, the cells were assayed for viability using the CTG assay. The dashed line indicates the non-linear fitting of the data to calculate an IC.sub.50 value.

[0044] FIG. 8 is a schematic overview of the functional assay for screening siRNA effects on cell proliferation to facilitate quantification of the effects of knocking down CD320 and LRP2 on cell proliferation. Cells were plated in a 24-well plate. The next day, the cells were transfected with siRNAs targeting CD320 (OSC17, OSC47) and/or targeting LRP2 (OSL231, OSL245), or a control siRNA (OSS2). The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. In addition, in a small subset of the wells, cells were only treated with doxorubicin as a positive control for toxicity. At the end of the study, the cell lines are analyzed for cell growth by the CTG assay.

[0045] FIGS. 9A-E illustrate graphs of the percent cell survival of siCD320 and siLRP2 on cell proliferation-Cell lines representative of several types of cancers (lung, brain) or normal fibroblasts were transfected with individual or combinations of siRNAs targeting CD320 (OSC17, OSC47) or LRP2 (OSL231, OSL245), individually at 20 nM or in combination (10 nM each), or a negative control siRNA (OSS2) (20 nM) as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

[0046] FIGS. 10A-E illustrate graphs of the effects of siCD320 and siLRP2 on cell proliferation-Cell lines representative of several types of cancers (breast, prostate, skin) were transfected with individual or combinations of siRNAs targeting CD320 (OSC17, OSC47) or LRP2 (OSL231, OSL245) as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

[0047] FIGS. 11A-B illustrate the effects of siCD320 and siLRP2 molar proportions on cell proliferation with different molar proportions of siRNA targeting CD320 and siRNA targeting LRP2. Cell lines representative of two types of cancers (breast, prostate) were transfected with different proportions of siRNAs targeting CD320 (OSC17) or LRP2 (OSL245) (0-20 nM) or a negative control siRNA (OSS2) as indicated. Cells were repeatedly transfected for efficient toxicity then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

[0048] FIGS. 12A-B illustrate graphs of the duration of the knockdown effect for siCD320 and siLRP2 on MDA-MD-231 cells. A representative breast cancer cell line (MDA-MD-231) was transfected on Day 0 with 20 nM of an siRNA targeting CD320 (OSC17) or an siRNA targeting LRP2 (OSL245) or a negative control siRNA (OSS2) and the percentage of protein knockdown was analyzed daily over a period of five days by western blot. Protein levels were normalized to the negative control (OSS2).

[0049] FIG. 13 is a schematic of polyethylenimine (PEI) and siRNA complexation. PEI and siRNAs are mixed together. Subsequently, polyplexes (a nanoparticle, broadly speaking) of the PEI-siRNA complex form, which are able to enter the cell.

[0050] FIG. 14 is a schematic that illustrates that siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the guide sequence of the siRNA is complementary to a mRNA expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are separated via the RISC/AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse activity, resulting in mRNA degradation, and the protein encoded by the mRNA is not produced. This causes the knockdown effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells.

[0051] FIGS. 15A-B illustrate graphs of A172 cell line or MDA-MD-435S cell lines treated with control siRNA (OSS1, OSS2) and siRNA directed to CD320 mRNA (OSC17, OSC47) and siRNA directed to LRP2 mRNA (OSL231, OSL245) to determine the effectiveness of INTERFERin, a polyethanolamine transfection reagent, in delivering siRNAs to cancer cells.

[0052] FIGS. 16A-D illustrate plated cells showing the effects of siCD320 and siLRP2 on four cell lines. Cell lines representative of four types of cancers (breast, two prostate, skin) were transfected with siRNAs targeting CD320 (OSC17) or LRP2 (OSL245) individually at 20 nM or in combination (10 nM each) or a negative control siRNA (OSS2) (20 nM) as indicated. Cells were repeatedly transfected for efficient toxicity as in Table 9 and then analyzed by microscopy as indicated.

[0053] FIG. 17 illustrates a graphical depiction of CD320 mRNA. UTR references the untranslated region, and the CDS references the protein coding sequence.

[0054] FIG. 18 illustrates a graphical depiction of LRP2 mRNA UTR references the untranslated region, and the CDS references the protein coding sequence.

[0055] FIGS. 19A-G illustrates the structures for unnatural nucleotides which may be incorporated within the sequence of an RNAi. B represents a natural (G, C, A, U) RNA nucleobase, a DNA nucleobase, or an unnatural nucleobase. FIG. 19A shows certain chemical modifications to the ribose 2-position and phosphate moieties. FIG. 19B-D shows skeletal modifications to the ribose moiety that comprise bridging groups. FIG. 19E shows a deletion of the C2-C3 bond. FIG. 19F-G shows other skeletal modifications to the ribose moiety wherein a six-membered ring replaces the five-membered ring.

[0056] FIG. 20 illustrates a schematic for the in vivo murine xenograft model for breast cancer. MDA-MB-231 cells were implanted into the flank of NSG mice and grown to a volume of 70 mm.sup.3 after which siRNAs targeting CD320 (OSC17) and LRP2 (OSL245) were injected intratumorally once every fourth day.

DETAILED DESCRIPTION OF THE INVENTION

[0057] One or more embodiment of the present invention provides methods and RNAi compounds for modulating the expression of a CD320 gene and/or an LRP2 gene in a cell. In certain embodiments, expression of a CD320 gene and/or a LRP2 gene is reduced or inhibited using an CD320 and/or LRP2 specific RNAi. Such inhibition can be useful in treating disorders such as cancer and/or creating cell lines that are useful for screening drugs that treat cancer

[0058] The present invention also relates to a method for knocking down (partially or completely) the targeted genes.

[0059] One embodiment of the method of producing knockdown cells and organisms comprises introducing into a cell or organism in which a gene (referred to as a targeted gene) to be knocked down, an siRNA of about 16 to about 30 nucleotides (nt) that targets the gene and maintaining the resulting cell or organism under conditions under which RNAi occurs, resulting in degradation of the mRNA of the targeted gene, thereby producing knockdown cells or organisms. Knockdown cells and organisms produced by the present method are also the subject of embodiment of the present invention.

[0060] An embodiment of the present invention also relates to a method of examining or assessing the function of a gene in a cell or organism. In one embodiment, RNA of about 16 to about 30 nt which targets mRNA of the gene for degradation is introduced into a cell or organism in which RNAi occurs. The cell or organism is referred to as a test cell or organism. The cell or organism is referred to as a test cell organism. The test cell or organism is maintained under conditions under which degradation of mRNA of the gene occurs. The phenotype of the test cell or organism is then observed and compared to that of an appropriate control cell or organism, such as a corresponding cell or organism that is treated in the same manner except that the gene is not targeted. A 16 to 30 nt RNA that does not target the mRNA for degradation can be introduced into the control cell or organism in place of the siRNA introduced into the test cell or organism, although it is not necessary to do so. A difference between the phenotypes of the test and control cells or organisms provides information about the function of the degraded mRNA.

[0061] The RNA of about 16 to about 30 nucleotides is isolated or synthesized and then introduced into a cell or organism in which RNAi occurs (test cell or test organism). The test cell or test organism is maintained under conditions under which degradation of the mRNA occurs. The phenotype of the test cell or organism is then observed and compared to that of an appropriate control, such as a corresponding cell or organism that is treated in the same manner as the test cell or organism except that the targeted gene is not targeted. A difference between the phenotypes of the test and control cells or organisms provides information about the function of the targeted gene. The information provided may be sufficient to identify (define) the function of the gene or may be used in conjunction with information obtained from other assays or analyses to do so.

[0062] An embodiment of the present invention also encompasses a method of treating a disease or condition associated with the presence of a protein in an individual, comprising administering to the individual RNA of from about 16 to about 30 nucleotides which targets the mRNA of the protein (the mRNA that encodes the protein) for degradation. As a result, the protein is not produced or is not produced to the extent it would be in the absence of the treatment.

[0063] FIG. 14 shows that siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the sequence of the siRNA is complementary to a mRNA expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are unwound via the RNA-induced silencing complex (RISC), whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity. The end result is that the mRNA targeted by the siRNA is degraded, and the protein encoded by the mRNA is not produced. This causes the knockdown effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells.

[0064] In one embodiment, at least one strand of the RNA molecule has a 3 overhang from about 1 to about 6 nucleotides (e.g., pyrimidine nucleotides, purine nucleotides) in length. In other embodiments, the 3 overhang is from about 1 to about 5 nucleotides, from about 1 to about 3 nucleotides and from about 2 to about 4 nucleotides in length or, for example, the overhang can be up to 14 nucleotides if the guide strand were a 27-mer. In one embodiment the RNA molecule is double stranded, one strand has a 3 overhang and the other strand can be blunt-ended or have an overhang. In the embodiment in which the RNA molecule is double stranded and both strands comprise an overhang, the length of the overhangs may be the same or different for each strand. In a particular embodiment, the RNA of the present invention comprises 21-27 nucleotide strands which are Watson-Crick paired and which have overhangs of from about 1 to about 3, particularly about 2, nucleotides on both 3 ends of the RNA. In order to further enhance the stability of the RNA of the present invention, the 3 overhangs can be stabilized against degradation. In one embodiment, the RNA is stabilized by including purine nucleotides, such as adenosine or guanosine nucleotides. Alternatively, substitution of pyrimidine nucleotides by unnatural nucleotides, e.g., substitution of uridine 2 nucleotide 3 overhangs by 2-deoxythymidine, is tolerated and does not affect the efficiency of RNAi. The absence of a 2 hydroxyl significantly enhances the nuclease resistance of the overhang in tissue culture medium. The 3-overhangs can be further stabilized by introduction of phosphorothioate groups in place of the phosphodiesters.

[0065] The 16-30 nt RNA molecules of the present invention can be obtained using a number of techniques known to those of skill in the art. For example, the RNA can be chemically synthesized or recombinantly produced using methods known in the art.

[0066] In order that the present invention may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention.

[0067] The articles a and an are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, an element means one element or more than one element, e.g., a plurality of elements.

[0068] The term including is used herein to mean, and is used interchangeably with, the phrase including but not limited to.

[0069] The term or is used herein to mean, and is used interchangeably with, the term and/or, unless context clearly indicates otherwise.

[0070] As used herein, CD320 refers to the gene or protein. CD320 is also known as 8D6 antigen, CD320 antigen, 8D6A, transcobalamin receptor, FDC-SM-8D6, FDC-Signaling Molecule 8D6, 8D6, TCBLR, TCbIR, TCN2R. The term CD320 includes human CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_016579.4 and NM_001165895.2; mouse CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_019421.3; rat CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_001014201.1. Additional examples of CD320 mRNA sequences are readily available using, e.g., GenBank. Additional information is found at FIG. 17.

[0071] The CD320 DNA sequence from Homo sapiens is as follows: >NM_016579.4 Homo sapiens CD320 molecule (CD320), transcript variant 1, DNA

TABLE-US-00006 (SEQIDNO.935) GTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCGGC GCCGCTGTGGGGACAGCATGAGCGGCGGTTGGATGGCGCAGGTTGGAGC GTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGCTCGGCCTC GGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTTTCCACCCCGACCTCTG CCCAGGCCGCAGGCCCCAGCTCAGGCTCGTGCCCACCCACCAAGTTCCA GTGCCGCACCAGTGGCTTATGCGTGCCCCTCACCTGGCGCTGCGACAGG GACTTGGACTGCAGCGATGGCAGCGATGAGGAGGAGTGCAGGATTGAGC CATGTACCCAGAAAGGGCAATGCCCACCGCCCCCTGGCCTCCCCTGCCC CTGCACCGGCGTCAGTGACTGCTCTGGGGGAACTGACAAGAAACTGCGC AACTGCAGCCGCCTGGCCTGCCTAGCAGGCGAGCTCCGTTGCACGCTGA GCGATGACTGCATTCCACTCACGTGGCGCTGCGACGGCCACCCAGACTG TCCCGACTCCAGCGACGAGCTCGGCTGTGGAACCAATGAGATCCTCCCG GAAGGGGATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAGTGTCA CCTCTCTCAGGAATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAG TGTCCCCTCTGTCGGGAATGCCACATCCTCCTCTGCCGGAGACCAGTCT GGAAGCCCAACTGCCTATGGGGTTATTGCAGCTGCTGCGGTGCTCAGTG CAAGCCTGGTCACCGCCACCCTCCTCCTTTTGTCCTGGCTCCGAGCCCA GGAGCGCCTCCGCCCACTGGGGTTACTGGTGGCCATGAAGGAGTCCCTG CTGCTGTCAGAACAGAAGACCTCGCTGCCCTGAGGACAAGCACTTGCCA CCACCGTCACTCAGCCCTGGGCGTAGCCGGACAGGAGGAGAGCAGTGAT GCGGATGGGTACCCGGGCACACCAGCCCTCAGAGACCTGAGCTCTTCTG GCCACGTGGAACCTCGAACCCGAGCTCCTGCAGAAGTGGCCCTGGAGAT TGAGGGTCCCTGGACACTCCCTATGGAGATCCGGGGAGCTAGGATGGGG AACCTGCCACAGCCAGAACTGAGGGGCTGGCCCCAGGCAGCTCCCAGGG GGTAGAACGGCCCTGTGCTTAAGACACTCCTGCTGCCCCGTCTGAGGGT GGCGATTAAAGTTGCTTCACATCCTCAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAA.

[0072] A protein sequence from CD320 derived from the mRNA sequence above is as follows:

TABLE-US-00007 (SEQIDNO.936) >sp|Q9NPF0|CD320_HUMANCD320antigenOS=Homo sapiensOX=9606GN=CD320PE=1SV=1 MSGGWMAQVGAWRTGALGLALLLLLGLGLGLEAAASPLSTPTSAQAAGP SSGSCPPTKFQCRTSGLCVPLTWRCDRDLDCSDGSDEEECRIEPCTQKG QCPPPPGLPCPCTGVSDCSGGTDKKLRNCSRLACLAGELRCTLSDDCIP LTWRCDGHPDCPDSSDELGCGTNEILPEGDATTMGPPVTLESVTSLRNA TTMGPPVTLESVPSVGNATSSSAGDQSGSPTAYGVIAAAAVLSASLVTA TLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP

[0073] The CD320 DNA sequence from Homo sapiens is as follows: >NM_001165895.2 Homo sapiens CD320 molecule (CD320), transcript variant 2, DNA

TABLE-US-00008 (SEQIDNO.937) GCGTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCG GCGCCGCTGTGGGGACAGCATGAGCGGCGGTTGGATGGCGCAGGTTGGA GCGTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGCTCGGCC TCGGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTTTCCACCCCGACCTC TGCCCAGGCCGCAGGGATTGAGCCATGTACCCAGAAAGGGCAATGCCCA CCGCCCCCTGGCCTCCCCTGCCCCTGCACCGGCGTCAGTGACTGCTCTG GGGGAACTGACAAGAAACTGCGCAACTGCAGCCGCCTGGCCTGCCTAGC AGGCGAGCTCCGTTGCACGCTGAGCGATGACTGCATTCCACTCACGTGG CGCTGCGACGGCCACCCAGACTGTCCCGACTCCAGCGACGAGCTCGGCT GTGGAACCAATGAGATCCTCCCGGAAGGGGATGCCACAACCATGGGGCC CCCTGTGACCCTGGAGAGTGTCACCTCTCTCAGGAATGCCACAACCATG GGGCCCCCTGTGACCCTGGAGAGTGTCCCCTCTGTCGGGAATGCCACAT CCTCCTCTGCCGGAGACCAGTCTGGAAGCCCAACTGCCTATGGGGTTAT TGCAGCTGCTGCGGTGCTCAGTGCAAGCCTGGTCACCGCCACCCTCCTC CTTTTGTCCTGGCTCCGAGCCCAGGAGCGCCTCCGCCCACTGGGGTTAC TGGTGGCCATGAAGGAGTCCCTGCTGCTGTCAGAACAGAAGACCTCGCT GCCCTGAGGACAAGCACTTGCCACCACCGTCACTCAGCCCTGGGCGTAG CCGGACAGGAGGAGAGCAGTGATGCGGATGGGTACCCGGGCACACCAGC CCTCAGAGACCTGAGCTCTTCTGGCCACGTGGAACCTCGAACCCGAGCT CCTGCAGAAGTGGCCCTGGAGATTGAGGGTCCCTGGACACTCCCTATGG AGATCCGGGGAGCTAGGATGGGGAACCTGCCACAGCCAGAACTGAGGGG CTGGCCCCAGGCAGCTCCCAGGGGGTAGAACGGCCCTGTGCTTAAGACA CTCCTGCTGCCCCGTCTGAGGGTGGCAATTAAAGTTGCTTCACATCCTC

[0074] A protein sequence from CD320 derived from the DNA sequence above is as follows:

TABLE-US-00009 (SEQIDNO.938) >sp|Q9NPF0-2|CD320_HUMANIsoform2ofCD320 antigenOS=HomosapiensOX=9606GN=CD320 MSGGWMAQVGAWRTGALGLALLLLLGLGLGLEAAASPLSTPTSAQAAGI EPCTQKGQCPPPPGLPCPCTGVSDCSGGTDKKLRNCSRLACLAGELRCT LSDDCIPLTWRCDGHPDCPDSSDELGCGTNEILPEGDATTMGPPVTLES VTSLRNATTMGPPVTLESVPSVGNATSSSAGDQSGSPTAYGVIAAAAVL SASLVTATLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP

[0075] Further, as used herein, LRP2 refers to the gene or protein. LRP2 is also known as megalin, LRP-2, Glycoprotein 330, DBS, GP330, Gp330, Calcium Sensor Protein, Heymann Nephritis Antigen Homolog, Low-Density Lipoprotein Receptor-Related Protein 2, EC 1.1.2.3, EC 3.4.21.9, LDL receptor related protein 2. The term LRP2 includes human LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_004525.3; mouse LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_001081088.2; rat LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_030827.1. Additional examples of LRP2 mRNA sequences are readily available using, e.g., GenBank. Additional information is found at FIG. 18.

[0076] One example of LRP2 is: >NM_004525.3 Homo sapiens LDL receptor related protein 2 (LRP2), DNA:

TABLE-US-00010 (SEQIDNO.939) GGTCTAAAGGGCTTTATGCACTGTCTGGAGGGTGGGGACTGGCGCGGGTAGAAAACGGGATGCCTCGGGC GTGGGGGCAGGCTTTTGGCCACTAGGAGCTGGCGGAGGTGCAGACCTAAAGGAGCGTTCGCTAGCAGAGG CGCTGCCGGTGCGGTGTGCTACGCGCGCCCACCTCCCGGGGAAGGAACGGCGAGGCCGGGGACCGTCGCG GAGATGGATCGCGGGCCGGCAGCAGTGGCGTGCACGCTGCTCCTGGCTCTCGTCGCCTGCCTAGCGCCGG CCAGTGGCCAAGAATGTGACAGTGCGCATTTTCGCTGTGGAAGTGGGCATTGCATCCCTGCAGACTGGAG GTGTGATGGGACCAAAGACTGTTCAGATGACGCGGATGAAATTGGCTGCGCTGTTGTGACCTGCCAGCAG GGCTATTTCAAGTGCCAGAGTGAGGGACAATGCATCCCCAACTCCTGGGTGTGTGACCAAGATCAAGACT GTGATGATGGCTCAGATGAACGTCAAGATTGCTCACAAAGTACATGCTCAAGTCATCAGATAACATGCTC CAATGGTCAGTGTATCCCAAGTGAATACAGGTGCGACCACGTCAGAGACTGCCCCGATGGAGCTGATGAG AATGACTGCCAGTACCCAACATGTGAGCAGCTTACTTGTGACAATGGGGCCTGCTATAACACCAGTCAGA AGTGTGATTGGAAAGTTGATTGCAGGGACTCCTCAGATGAAATCAACTGCACTGAGATATGCTTGCACAA TGAGTTTTCATGTGGCAATGGAGAGTGTATCCCTCGTGCTTATGTCTGTGACCATGACAATGATTGCCAA GACGGCAGTGACGAACATGCTTGCAACTATCCGACCTGCGGTGGTTACCAGTTCACTTGCCCCAGTGGCC GATGCATTTATCAAAACTGGGTTTGTGATGGAGAAGATGACTGTAAAGATAATGGAGATGAAGATGGATG TGAAAGCGGTCCTCATGATGTTCATAAATGTTCCCCAAGAGAATGGTCTTGCCCAGAGTCGGGACGATGC ATCTCCATTTATAAAGTTTGTGATGGGATTTTAGATTGCCCAGGAAGAGAAGATGAAAACAACACTAGTA CCGGAAAATACTGTAGTATGACTCTGTGCTCTGCCTTGAACTGCCAGTACCAGTGCCATGAGACGCCGTA TGGAGGAGCGTGTTTTTGTCCCCCAGGTTATATCATCAACCACAATGACAGCCGTACCTGTGTTGAGTTT GATGATTGCCAGATATGGGGAATTTGTGACCAGAAGTGTGAAAGCCGACCTGGCCGTCACCTGTGCCACT GTGAAGAAGGGTATATCTTGGAGCGTGGACAGTATTGCAAAGCTAATGATTCCTTTGGCGAGGCCTCCAT TATCTTCTCCAATGGTCGGGATTTGTTAATTGGTGATATTCATGGAAGGAGCTTCCGGATCCTAGTGGAG TCTCAGAATCGTGGAGTGGCCGTGGGTGTGGCTTTCCACTATCACCTGCAAAGAGTTTTTTGGACAGACA CCGTGCAAAATAAGGTTTTTTCAGTTGACATTAATGGTTTAAATATCCAAGAGGTTCTCAATGTTTCTGT TGAAACCCCAGAGAACCTGGCTGTGGACTGGGTTAATAATAAAATCTATCTAGTGGAAACCAAGGTCAAC CGCATAGATATGGTAAATTTGGATGGAAGCTATCGGGTTACCCTTATAACTGAAAACTTGGGGCATCCTA GAGGAATTGCCGTGGACCCAACTGTTGGTTATTTATTTTTCTCAGATTGGGAGAGCCTTTCTGGGGAACC TAAGCTGGAAAGGGCATTCATGGATGGCAGCAACCGTAAAGACTTGGTGAAAACAAAGCTGGGATGGCCT GCTGGGGTAACTCTGGATATGATATCGAAGCGTGTTTACTGGGTTGACTCTCGGTTTGATTACATTGAAA CTGTAACTTATGATGGAATTCAAAGGAAGACTGTAGTTCATGGAGGCTCCCTCATTCCTCATCCCTTTGG AGTAAGCTTATTTGAAGGTCAGGTGTTCTTTACAGATTGGACAAAGATGGCCGTGCTGAAGGCAAACAAG TTCACAGAGACCAACCCACAAGTGTACTACCAGGCTTCCCTGAGGCCCTATGGAGTGACTGTTTACCATT CCCTCAGACAGCCCTATGCTACCAATCCGTGTAAAGATAACAATGGGGGCTGTGAGCAGGTCTGTGTCCT CAGCCACAGAACAGATAATGATGGTTTGGGTTTCCGTTGCAAGTGCACATTCGGCTTCCAACTGGATACA GATGAGCGCCACTGCATTGCTGTTCAGAATTTCCTCATTTTTTCATCCCAAGTTGCTATTCGTGGGATCC CGTTCACCTTGTCTACCCAGGAAGATGTCATGGTTCCAGTTTCGGGGAATCCTTCTTTCTTTGTCGGGAT TGATTTTGACGCCCAGGACAGCACTATCTTTTTTTCAGATATGTCAAAACACATGATTTTTAAGCAAAAG ATTGATGGCACAGGAAGAGAAATTCTCGCAGCTAACAGGGTGGAAAATGTTGAAAGTTTGGCTTTTGATT GGATTTCAAAGAATCTCTATTGGACAGACTCTCATTACAAGAGTATCAGTGTCATGAGGCTAGCTGATAA AACGAGACGCACAGTAGTTCAGTATTTAAATAACCCACGGTCGGTGGTAGTTCATCCTTTTGCCGGGTAT CTATTCTTCACTGATTGGTTCCGTCCTGCTAAAATTATGAGAGCATGGAGTGACGGATCTCACCTCTTGC CTGTAATAAACACTACTCTTGGATGGCCCAATGGCTTGGCCATCGATTGGGCTGCTTCACGATTGTACTG GGTAGATGCCTATTTTGATAAAATTGAGCACAGCACCTTTGATGGTTTAGACAGAAGAAGACTGGGCCAT ATAGAGCAGATGACACATCCGTTTGGACTTGCCATCTTTGGAGAGCATTTATTTTTTACTGACTGGAGAC TGGGTGCCATTATTCGAGTCAGGAAAGCAGATGGTGGAGAAATGACAGTTATCCGAAGTGGCATTGCTTA CATACTGCATTTGAAATCGTATGATGTCAACATCCAGACTGGTTCTAACGCCTGTAATCAACCCACGCAT CCTAACGGTGACTGCAGCCACTTCTGCTTCCCGGTGCCAAATTTCCAGCGAGTGTGTGGGTGCCCTTATG GAATGAGGCTGGCTTCCAATCACTTGACATGCGAGGGGGACCCAACCAATGAACCACCCACAGAGCAGTG TGGCTTATTTTCCTTCCCCTGTAAAAATGGCAGATGTGTGCCCAATTACTATCTCTGTGATGGAGTCGAT GATTGTCATGATAACAGTGATGAGCAACTATGTGGCACACTTAATAATACCTGTTCATCTTCGGCGTTCA CCTGTGGCCATGGGGAGTGCATTCCTGCACACTGGCGCTGTGACAAACGCAACGACTGTGTGGATGGCAG TGATGAGCACAACTGCCCCACCCACGCACCTGCTTCCTGCCTTGACACCCAATACACCTGTGATAATCAC CAGTGTATCTCAAAGAACTGGGTCTGTGACACAGACAATGATTGTGGGGATGGATCTGATGAAAAGAACT GCAATTCGACAGAGACATGCCAACCTAGTCAGTTTAATTGCCCCAATCATCGATGTATTGACCTATCGTT TGTCTGTGATGGTGACAAGGATTGTGTTGATGGATCTGATGAGGTTGGTTGTGTATTAAACTGTACTGCT TCTCAATTCAAGTGTGCCAGTGGGGATAAATGTATTGGCGTCACAAATCGTTGTGATGGTGTTTTTGATT GCAGTGACAACTCGGATGAAGCAGGCTGTCCAACCAGGCCTCCTGGTATGTGCCACTCAGATGAATTTCA GTGCCAAGAAGATGGTATCTGCATCCCGAACTTCTGGGAATGTGATGGGCATCCAGACTGCCTCTATGGA TCTGATGAGCACAATGCCTGTGTCCCCAAGACTTGCCCTTCATCATATTTCCACTGTGACAACGGAAACT GCATCCACAGGGCATGGCTCTGTGATCGGGACAATGACTGCGGGGATATGAGTGATGAGAAGGACTGCCC TACTCAGCCCTTTCGCTGTCCTAGTTGGCAATGGCAGTGTCTTGGCCATAACATCTGTGTGAATCTGAGT GTAGTGTGTGATGGCATCTTTGACTGCCCCAATGGGACAGATGAGTCCCCACTTTGCAATGGGAACAGCT GCTCAGATTTCAATGGTGGTTGTACTCACGAGTGTGTTCAAGAGCCCTTTGGGGCTAAATGCCTATGTCC ATTGGGATTCTTACTTGCCAATGATTCTAAGACCTGTGAAGACATAGATGAATGTGATATTCTAGGCTCT TGTAGCCAGCACTGTTACAATATGAGAGGTTCTTTCCGGTGCTCGTGTGATACAGGCTACATGTTAGAAA GTGATGGGAGGACTTGCAAAGTTACAGCATCTGAGAGTCTGCTGTTACTTGTGGCAAGTCAGAACAAAAT TATTGCCGACAGTGTCACCTCCCAGGTCCACAATATCTATTCATTGGTCGAGAATGGTTCTTACATTGTA GCTGTTGATTTTGATTCAATTAGTGGTCGTATCTTTTGGTCTGATGCAACTCAGGGTAAAACCTGGAGTG CGTTTCAAAATGGAACGGACAGAAGAGTGGTATTTGACAGTAGCATCATCTTGACTGAAACTATTGCAAT AGATTGGGTAGGTCGTAATCTTTACTGGACAGACTATGCTCTGGAAACAATTGAAGTCTCCAAAATTGAT GGGAGCCACAGGACTGTGCTGATTAGTAAAAACCTAACAAATCCAAGAGGACTAGCATTAGATCCCAGAA TGAATGAGCATCTACTGTTCTGGTCTGACTGGGGCCACCACCCTCGCATCGAGCGAGCCAGCATGGACGG CAGCATGCGCACTGTCATTGTCCAGGACAAGATCTTCTGGCCCTGCGGCTTAACTATTGACTACCCCAAC AGACTGCTCTACTTCATGGACTCCTATCTTGATTACATGGACTTTTGTGATTATAATGGACACCATCGGA GACAGGTGATAGCCAGTGATTTGATTATACGGCACCCCTATGCCCTAACTCTCTTTGAAGACTCTGTGTA CTGGACTGACCGTGCTACTCGTCGGGTTATGCGAGCCAACAAGTGGCATGGAGGGAACCAGTCAGTTGTA ATGTATAATATTCAATGGCCCCTTGGGATTGTTGCGGTTCATCCTTCGAAACAACCAAATTCCGTGAATC CATGTGCCTTTTCCCGCTGCAGCCATCTCTGCCTGCTTTCCTCACAGGGGCCTCATTTTTACTCCTGTGT TTGTCCTTCAGGATGGAGTCTGTCTCCTGATCTCCTGAATTGCTTGAGAGATGATCAACCTTTCTTAATA ACTGTAAGGCAACATATAATTTTTGGAATCTCCCTTAATCCTGAGGTGAAGAGCAATGATGCTATGGTCC CCATAGCAGGGATACAGAATGGTTTAGATGTTGAATTTGATGATGCTGAGCAATACATCTATTGGGTTGA AAATCCAGGTGAAATTCACAGAGTGAAGACAGATGGCACCAACAGGACAGTATTTGCTTCTATATCTATG GTGGGGCCTTCTATGAACCTGGCCTTAGATTGGATTTCAAGAAACCTTTATTCTACCAATCCTAGAACTC AGTCAATCGAGGTTTTGACACTCCACGGAGATATCAGATACAGAAAAACATTGATTGCCAATGATGGGAC AGCTCTTGGAGTTGGCTTTCCAATTGGCATAACTGTTGATCCTGCTCGTGGGAAGCTGTACTGGTCAGAC CAAGGAACTGACAGTGGGGTTCCTGCCAAGATCGCCAGTGCTAACATGGATGGCACATCTGTGAAAACTC TCTTTACTGGGAACCTCGAACACCTGGAGTGTGTCACTCTTGACATCGAAGAGCAGAAACTCTACTGGGC AGTCACTGGAAGAGGAGTGATTGAAAGAGGAAACGTGGATGGAACAGATCGAATGATCCTGGTACACCAG CTTTCCCACCCCTGGGGAATTGCAGTCCATGATTCTTTCCTTTATTATACTGATGAACAGTATGAGGTCA TTGAAAGAGTTGATAAGGCCACTGGGGCCAACAAAATAGTCTTGAGAGATAATGTTCCAAATCTGAGGGG TCTTCAAGTTTATCACAGACGCAATGCCGCCGAATCCTCAAATGGCTGTAGCAACAACATGAATGCCTGT CAGCAGATTTGCCTGCCTGTACCAGGAGGATTGTTTTCCTGCGCCTGTGCCACTGGATTTAAACTCAATC CTGATAATCGGTCCTGCTCTCCATATAACTCTTTCATTGTTGTTTCAATGCTGTCTGCAATCAGAGGCTT TAGCTTGGAATTGTCAGATCATTCAGAAACCATGGTGCCGGTGGCAGGCCAAGGACGAAACGCACTGCAT GTGGATGTGGATGTGTCCTCTGGCTTTATTTATTGGTGTGATTTTAGCAGCTCAGTGGCATCTGATAATG CGATCCGTAGAATTAAACCAGATGGATCTTCTCTGATGAACATTGTGACACATGGAATAGGAGAAAATGG AGTCCGGGGTATTGCAGTGGATTGGGTAGCAGGAAATCTTTATTTCACCAATGCCTTTGTTTCTGAAACA CTGATAGAAGTTCTGCGGATCAATACTACTTACCGCCGTGTTCTTCTTAAAGTCACAGTGGACATGCCTA GGCATATTGTTGTAGATCCCAAGAACAGATACCTCTTCTGGGCTGACTATGGGCAGAGACCAAAGATTGA GCGTTCTTTCCTTGACTGTACCAATCGAACAGTGCTTGTGTCAGAGGGCATTGTCACACCACGGGGCTTG GCAGTGGACCGAAGTGATGGCTACGTTTATTGGGTTGATGATTCTTTAGATATAATTGCAAGGATTCGTA TCAATGGAGAGAACTCTGAAGTGATTCGTTATGGCAGTCGTTACCCAACTCCTTATGGCATCACTGTTTT TGAAAATTCTATCATATGGGTAGATAGGAATTTGAAAAAGATCTTCCAAGCCAGCAAGGAACCAGAGAAC ACAGAGCCACCCACAGTGATAAGAGACAATATCAACTGGCTAAGAGATGTGACCATCTTTGACAAGCAAG TCCAGCCCCGGTCACCAGCAGAGGTCAACAACAACCCTTGCTTGGAAAACAATGGTGGGTGCTCTCATCT CTGCTTTGCTCTGCCTGGATTGCACACCCCAAAATGTGACTGTGCCTTTGGGACCCTGCAAAGTGATGGC AAGAATTGTGCCATTTCAACAGAAAATTTCCTCATCTTTGCCTTGTCTAATTCCTTGAGAAGCTTACACT TGGACCCTGAAAACCATAGCCCACCTTTCCAAACAATAAATGTGGAAAGAACTGTCATGTCTCTAGACTA TGACAGTGTAAGTGATAGAATCTACTTCACACAAAATTTAGCCTCTGGAGTTGGACAGATTTCCTATGCC ACCCTGTCTTCAGGGATCCATACTCCAACTGTCATTGCTTCAGGTATAGGGACTGCTGATGGCATTGCCT TTGACTGGATTACTAGAAGAATTTATTACAGTGACTACCTCAACCAGATGATTAATTCCATGGCTGAAGA TGGGTCTAACCGCACTGTGATAGCCCGCGTTCCAAAACCAAGAGCAATTGTGTTAGATCCCTGCCAAGGG TACCTGTACTGGGCTGACTGGGATACACATGCCAAAATCGAGAGAGCCACATTGGGAGGAAACTTCCGCG TACCCATTGTGAACAGCAGTCTGGTCATGCCCAGTGGGCTGACTCTGGACTATGAAGAGGACCTTCTCTA CTGGGTGGATGCTAGTCTGCAGAGGATTGAACGCAGCACTCTGACGGGCGTGGATCGTGAAGTCATTGTC AATGCAGCCGTTCATGCTTTTGGCTTGACTCTCTATGGCCAGTATATTTACTGGACTGACTTGTACACAC AAAGAATTTACCGAGCTAACAAATATGACGGGTCAGGTCAGATTGCAATGACCACAAATTTGCTCTCCCA GCCCAGGGGAATCAACACTGTTGTGAAGAACCAGAAACAACAGTGTAACAATCCTTGTGAACAGTTTAAT GGGGGCTGCAGCCATATCTGTGCACCAGGTCCAAATGGTGCCGAGTGCCAGTGTCCACATGAGGGCAACT GGTATTTGGCCAACAACAGGAAGCACTGCATTGTGGACAATGGTGAACGATGTGGTGCATCTTCCTTCAC CTGCTCCAATGGGCGCTGCATCTCGGAAGAGTGGAAGTGTGATAATGACAACGACTGTGGGGATGGCAGT GATGAGATGGAAAGTGTCTGTGCACTTCACACCTGCTCACCGACAGCCTTCACCTGTGCCAATGGGCGAT GTGTCCAATACTCTTACCGCTGTGATTACTACAATGACTGTGGTGATGGCAGTGATGAGGCAGGGTGCCT GTTCAGGGACTGCAATGCCACCACGGAGTTTATGTGCAATAACAGAAGGTGCATACCTCGTGAGTTTATC TGCAATGGTGTAGACAACTGCCATGATAATAACACTTCAGATGAGAAAAATTGCCCTGATCGCACTTGCC AGTCTGGATACACAAAATGTCATAATTCAAATATTTGTATTCCTCGCGTTTATTTGTGTGACGGAGACAA TGACTGTGGAGATAACAGTGATGAAAACCCTACTTATTGCACCACTCACACGTGCAGCAGCAGTGAGTTC CAATGCGCATCTGGGCGCTGTATTCCTCAACATTGGTATTGTGATCAAGAAACAGATTGTTTTGATGCCT CTGATGAACCTGCCTCTTGTGGTCACTCTGAGCGAACATGCCTAGCTGATGAGTTCAAGTGTGATGGTGG GAGGTGCATCCCAAGCGAATGGATCTGTGACGGTGATAATGACTGTGGGGATATGAGTGACGAGGATAAA AGGCACCAGTGTCAGAATCAAAACTGCTCGGATTCCGAGTTTCTCTGTGTAAATGACAGACCTCCGGACA GGAGGTGCATTCCCCAGTCTTGGGTCTGTGATGGCGATGTGGATTGTACTGACGGCTACGATGAGAATCA GAATTGCACCAGGAGAACTTGCTCTGAAAATGAATTCACCTGTGGTTACGGACTGTGTATCCCAAAGATA TTCAGGTGTGACCGGCACAATGACTGTGGTGACTATAGCGACGAGAGGGGCTGCTTATACCAGACTTGCC AACAGAATCAGTTTACCTGTCAGAACGGGCGCTGCATTAGTAAAACCTTCGTCTGTGATGAGGATAATGA CTGTGGAGACGGATCTGATGAGCTGATGCACCTGTGCCACACCCCAGAACCCACGTGTCCACCTCACGAG TTCAAGTGTGACAATGGGCGCTGCATCGAGATGATGAAACTCTGCAACCACCTAGATGACTGTTTGGACA ACAGCGATGAGAAAGGCTGTGGCATTAATGAATGCCATGACCCTTCAATCAGTGGCTGCGATCACAACTG CACAGACACCTTAACCAGTTTCTATTGTTCCTGTCGTCCTGGTTACAAGCTCATGTCTGACAAGCGGACT TGTGTTGATATTGATGAATGCACAGAGATGCCTTTTGTCTGTAGCCAGAAGTGTGAGAATGTAATAGGCT CCTACATCTGTAAGTGTGCCCCAGGCTACCTCCGAGAACCAGATGGAAAGACCTGCCGGCAAAACAGTAA CATCGAACCCTATCTCATTTTTAGCAACCGTTACTATTTGAGAAATTTAACTATAGATGGCTATTTTTAC TCCCTCATCTTGGAAGGACTGGACAATGTTGTGGCATTAGATTTTGACCGAGTAGAGAAGAGATTGTATT GGATTGATACACAGAGGCAAGTCATTGAGAGAATGTTTCTGAATAAGACAAACAAGGAGACAATCATAAA CCACAGACTACCAGCTGCAGAAAGTCTGGCTGTAGACTGGGTTTCCAGAAAGCTCTACTGGTTGGATGCC CGCCTGGATGGCCTCTTTGTCTCTGACCTCAATGGTGGACACCGCCGCATGCTGGCCCAGCACTGTGTGG ATGCCAACAACACCTTCTGCTTTGATAATCCCAGAGGACTTGCCCTTCACCCTCAATATGGGTACCTCTA CTGGGCAGACTGGGGTCACCGCGCATACATTGGGAGAGTAGGCATGGATGGAACCAACAAGTCTGTGATA ATCTCCACCAAGTTAGAGTGGCCTAATGGCATCACCATTGATTACACCAATGATCTACTCTACTGGGCAG ATGCCCACCTGGGTTACATAGAGTACTCTGATTTGGAGGGCCACCATCGACACACGGTGTATGATGGGGC ACTGCCTCACCCTTTCGCTATTACCATTTTTGAAGACACTATTTATTGGACAGATTGGAATACAAGGACA GTGGAAAAGGGAAACAAATATGATGGATCAAATAGACAGACACTGGTGAACACAACACACAGACCATTTG ACATCCATGTGTACCATCCATATAGGCAGCCCATTGTGAGCAATCCCTGTGGTACCAACAATGGTGGCTG TTCTCATCTCTGCCTCATCAAGCCAGGAGGAAAAGGGTTCACTTGCGAGTGTCCAGATGACTTCCGCACC CTTCAGCTGAGTGGCAGCACCTACTGCATGCCCATGTGCTCCAGCACCCAGTTCCTGTGCGCTAACAATG AAAAGTGCATTCCTATCTGGTGGAAATGTGATGGACAGAAAGACTGCTCAGATGGCTCTGATGAACTGGC CCTTTGCCCGCAGCGCTTCTGCCGACTGGGACAGTTCCAGTGCAGTGACGGCAACTGCACCAGCCCGCAG ACTTTATGCAATGCTCACCAAAATTGCCCTGATGGGTCTGATGAAGACCGTCTTCTTTGTGAGAATCACC ACTGTGACTCCAATGAATGGCAGTGCGCCAACAAACGTTGCATCCCAGAATCCTGGCAGTGTGACACATT TAACGACTGTGAGGATAACTCAGATGAAGACAGTTCCCACTGTGCCAGCAGGACCTGCCGGCCGGGCCAG TTTCGGTGTGCTAATGGCCGCTGCATCCCGCAGGCCTGGAAGTGTGATGTGGATAATGATTGTGGAGACC ACTCGGATGAGCCCATTGAAGAATGCATGAGCTCTGCCCATCTCTGTGACAACTTCACAGAATTCAGCTG CAAAACAAATTACCGCTGCATCCCAAAGTGGGCCGTGTGCAATGGTGTAGATGACTGCAGGGACAACAGT GATGAGCAAGGCTGTGAGGAGAGGACATGCCATCCTGTGGGGGATTTCCGCTGTAAAAATCACCACTGCA TCCCTCTTCGTTGGCAGTGTGATGGGCAAAATGACTGTGGAGATAACTCAGATGAGGAAAACTGTGCTCC CCGGGAGTGCACAGAGAGCGAGTTTCGATGTGTCAATCAGCAGTGCATTCCCTCGCGATGGATCTGTGAC CATTACAACGACTGTGGGGACAACTCAGATGAACGGGACTGTGAGATGAGGACCTGCCATCCTGAATATT TTCAGTGTACAAGTGGACATTGTGTACACAGTGAACTGAAATGCGATGGATCCGCTGACTGTTTGGATGC GTCTGATGAAGCTGATTGTCCCACACGCTTTCCTGATGGTGCATACTGCCAGGCTACTATGTTCGAATGC AAAAACCATGTTTGTATCCCGCCATATTGGAAATGTGATGGCGATGATGACTGTGGCGATGGTTCAGATG AAGAACTTCACCTGTGCTTGGATGTTCCCTGTAATTCACCAAACCGTTTCCGGTGTGACAACAATCGCTG CATTTATAGTCATGAGGTGTGCAATGGTGTGGATGACTGTGGAGATGGAACTGATGAGACAGAGGAGCAC TGTAGAAAACCGACCCCTAAACCTTGTACAGAATATGAATATAAGTGTGGCAATGGGCATTGCATTCCAC ATGACAATGTGTGTGATGATGCCGATGACTGTGGTGACTGGTCCGATGAACTGGGTTGCAATAAAGGAAA AGAAAGAACATGTGCTGAAAATATATGCGAGCAAAATTGTACCCAATTAAATGAAGGAGGATTTATCTGC TCCTGTACAGCTGGGTTCGAAACCAATGTTTTTGACAGAACCTCCTGTCTAGATATCAATGAATGTGAAC AATTTGGGACTTGTCCCCAGCACTGCAGAAATACCAAAGGAAGTTATGAGTGTGTCTGTGCTGATGGCTT CACGTCTATGAGTGACCGCCCTGGAAAACGATGTGCAGCTGAGGGTAGCTCTCCTTTGTTGCTACTGCCT GACAATGTCCGAATTCGAAAATATAATCTCTCATCTGAGAGGTTCTCAGAGTATCTTCAAGATGAGGAAT ATATCCAAGCTGTTGATTATGATTGGGATCCCAAGGACATAGGCCTCAGTGTTGTGTATTACACTGTGCG AGGGGAGGGCTCTAGGTTTGGTGCTATCAAACGTGCCTACATCCCCAACTTTGAATCCGGCCGCAATAAT CTTGTGCAGGAAGTTGACCTGAAACTGAAATACGTAATGCAGCCAGATGGAATAGCAGTGGACTGGGTTG GAAGGCATATTTACTGGTCAGATGTCAAGAATAAACGCATTGAGGTGGCTAAACTTGATGGAAGGTACAG AAAGTGGCTGATTTCCACTGACCTGGACCAACCAGCTGCTATTGCTGTGAATCCCAAACTAGGGCTTATG TTCTGGACTGACTGGGGAAAGGAACCTAAAATCGAGTCTGCCTGGATGAATGGAGAGGACCGCAACATCC TGGTTTTCGAGGACCTTGGTTGGCCAACTGGCCTTTCTATCGATTATTTGAACAATGACCGAATCTACTG GAGTGACTTCAAGGAGGACGTTATTGAAACCATAAAATATGATGGGACTGATAGGAGAGTCATTGCAAAG GAAGCAATGAACCCTTACAGCCTGGACATCTTTGAAGACCAGTTATACTGGATATCTAAGGAAAAGGGAG AAGTATGGAAACAAAATAAATTTGGGCAAGGAAAGAAAGAGAAAACGCTGGTAGTGAACCCTTGGCTCAC TCAAGTTCGAATCTTTCATCAACTCAGATACAATAAGTCAGTGCCCAACCTTTGCAAACAGATCTGCAGC CACCTCTGCCTTCTGAGACCTGGAGGATACAGCTGTGCCTGTCCCCAAGGCTCCAGCTTTATAGAGGGGA GCACCACTGAGTGTGATGCAGCCATCGAACTGCCTATCAACCTGCCCCCCCCATGCAGGTGCATGCACGG AGGAAATTGCTATTTTGATGAGACTGACCTCCCCAAATGCAAGTGTCCTAGCGGCTACACCGGAAAATAT TGTGAAATGGCGTTTTCAAAAGGCATCTCTCCAGGAACAACCGCAGTAGCTGTGCTGTTGACAATCCTCT TGATCGTCGTAATTGGAGCTCTGGCAATTGCAGGATTCTTCCACTATAGAAGGACCGGCTCCCTTTTGCC TGCTCTGCCCAAGCTGCCAAGCTTAAGCAGTCTCGTCAAGCCCTCTGAAAATGGGAATGGGGTGACCTTC AGATCAGGGGCAGATCTTAACATGGATATTGGAGTGTCTGGTTTTGGACCTGAGACTGCTATTGACAGGT CAATGGCAATGAGTGAAGACTTTGTCATGGAAATGGGGAAGCAGCCCATAATATTTGAAAACCCAATGTA CTCAGCCAGAGACAGTGCTGTCAAAGTGGTTCAGCCAATCCAGGTGACTGTATCTGAAAATGTGGATAAT AAGAATTATGGAAGTCCCATAAACCCTTCTGAGATAGTTCCAGAGACAAACCCAACTTCACCAGCTGCTG ATGGAACTCAGGTGACAAAATGGAATCTCTTCAAACGAAAATCTAAACAAACTACCAACTTTGAAAATCC AATCTATGCACAGATGGAGAACGAGCAAAAGGAAAGTGTTGCTGCGACACCACCTCCATCACCTTCGCTC CCTGCTAAGCCTAAGCCTCCTTCGAGAAGAGACCCAACTCCAACCTATTCTGCAACAGAAGACACTTTTA AAGACACCGCAAATCTTGTTAAAGAAGACTCTGAAGTATAGCTATACCAGCTATTTAGGGAATAATTAGA AACACACTTTTGCACATATATTTITTACAAACAGATGAAAAAAGTTAACATTCAGTACTTTATGAAAAAA ATATATTTTTCCCTGTTTGCCTATAGTTGGAGGTATCCTGTGTGTCTTTTTTTACTTATGCCGTCTCATA TTTTTACAAATAATTATCACAATGTACTATATGTATATCTTTGCACTGAAGTTGTCTGAAGGTAATACTA TAAATATATTGTATATTTGTAAATTTTGGAAAGATTATCCTGTTACTGAATTTGCTAATAAAGATGTCTG CTGATTTGGTTGGTGATCATTATAGTAAATGATCCAACAAGAAAAGGAATTGACTGGGGACCTTTAGCCG TGTCTAAAGAAGAGGCACCACTCATATTTCCTATAAAATTATCTAGGAAAGGAATCCAGGCCCCGCTCTT GGGTCCATTTTTACACATTAGCACTTAATTAATGTTCAATATTACATGTCAATTTGATTAATGGCTATGT TGATAGGGGCCACTATGTGTTGTATAGACATCTGGACTTGACTGTAGACTCCTCAGATAATACAGAAGGT AGGAAAAGCAATTCAGTTTGGCCCTTCTGTGTGTTGGCATTGTCTAACCAGAACTCTCTGTTTCATGTGT GTTCTCTCACTAGCTGCCAAGACAACATTTTTATTTGTGATGTCTATGAGGAAATCCCATATCATTAAGT GCCAGTGTCCTGCATTGAGTTTGTGGTTAATTAAATGAGCTCTTCTGCTGATGGACCCTGGAGCAATTTC TCCCCTCACCTGACATTCAAGGTGGTCACCTGCCCTAGTAGTTGGAGCTCAGTAGCTGAATTTCTGAAAC CAAATCTGTGTCTTCATAAAATAAGGTGCAAAAAAAAAAAATACCAGTTAAGTAAAGCCTCAACTGGGTT TTTGTTTCTATGAAAATATCATTATAATCACTATTTATTTCCTAAGTTGAACCTGAATAGAAAGGGAAAC CATTCTTATTAAGCTTTTTATTAGGCCCTGTGGCTAAATGTGTACATTTATATTAGAATGTACTGTACAG TCCAGATCTTTTCTTTAATTCTTATTGGTTTTTTTTTTTTTAGAGATGGAGTCTTGCTATATTGCCAAGG CTGATCTTGAAGTCCTGGGCTCAAGTGATCCTCCCACCTCAGCCTCCTGAGTGGTTGGGGTTACGGGCGT GAGCCACTGTGCCTGGCTTCCAGCTCTCCTCTTAAATAGTGGGTATAGTCTGCACAACAGGAACCATGGC AGGAATATACACTTTCCCATAGCAAATAGCATACCTGACTCTCTGTGCTAATATTGCACATTTGTTAAAC AATGAATGAATGGATGGATGGATGGATGGATGAATGAATGAAACATATACTACTGATTATTTTATTCCAG AGTTCTCAAAATATTTGTTGCTGATATTTTGAGTGCTGACTGTAATTACTTTGATTAGATAAACAACTGG AAATAATGCTGCTGAAAAAGTTCTAATAAATGTGTATTTTATCAGA.

[0077] One example of a protein sequence from the above LRP2 DNA is:

TABLE-US-00011 >sp|P98164|LRP2_HUMANLow-densitylipoproteinreceptor-related protein2OS=HomosapiensOX=9606GN=LRP2PE=1SV=3 (SEQIDNO.940) MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDGTKDCSDDADEI GCAVVTCQQGYFKCQSEGQCIPNSWVCDQDQDCDDGSDERQDCSQSTCSSHQITCSNGQC IPSEYRCDHVRDCPDGADENDCQYPTCEQLTCDNGACYNTSQKCDWKVDCRDSSDEINCT EICLHNEFSCGNGECIPRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWV CDGEDDCKDNGDEDGCESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPGREDENN TSTGKYCSMTLCSALNCQYQCHETPYGGACFCPPGYIINHNDSRTCVEFDDCQIWGICDQ KCESRPGRHLCHCEEGYILERGQYCKANDSFGEASIIFSNGRDLLIGDIHGRSFRILVES QNRGVAVGVAFHYHLQRVFWTDTVQNKVFSVDINGLNIQEVLNVSVETPENLAVDWVNNK IYLVETKVNRIDMVNLDGSYRVTLITENLGHPRGIAVDPTVGYLFFSDWESLSGEPKLER AFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDSRFDYIETVTYDGIQRKTVVHGGSL IPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQVYYQASLRPYGVTVYHSLRQPYAT NPCKDNNGGCEQVCVLSHRTDNDGLGFRCKCTFGFQLDTDERHCIAVQNFLIFSSQVAIR GIPFTLSTQEDVMVPVSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQKIDGTGREILAA NRVENVESLAFDWISKNLYWTDSHYKSISVMRLADKTRRTVVQYLNNPRSVVVHPFAGYL FFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAASRLYWVDAYFDKIEHSTFD GLDRRRLGHIEQMTHPFGLAIFGEHLFFTDWRLGAIIRVRKADGGEMTVIRSGIAYILHL KSYDVNIQTGSNACNQPTHPNGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNE PPTEQCGLFSFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNNTCSSSAFTCGHGECI PAHWRCDKRNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWVCDTDNDCGDGSDE KNCNSTETCQPSQFNCPNHRCIDLSFVCDGDKDCVDGSDEVGCVLNCTASQFKCASGDKC IGVTNRCDGVFDCSDNSDEAGCPTRPPGMCHSDEFQCQEDGICIPNFWECDGHPDCLYGS DEHNACVPKTCPSSYFHCDNGNCIHRAWLCDRDNDCGDMSDEKDCPTQPFRCPSWQWQCL GHNICVNLSVVCDGIFDCPNGTDESPLCNGNSCSDFNGGCTHECVQEPFGAKCLCPLGFL LANDSKTCEDIDECDILGSCSQHCYNMRGSFRCSCDTGYMLESDGRTCKVTASESLLLLV ASQNKIIADSVTSQVHNIYSLVENGSYIVAVDFDSISGRIFWSDATQGKTWSAFQNGTDR RVVFDSSIILTETIAIDWVGRNLYWTDYALETIEVSKIDGSHRTVLISKNLTNPRGLALD PRMNEHLLFWSDWGHHPRIERASMDGSMRTVIVQDKIFWPCGLTIDYPNRLLYFMDSYLD YMDFCDYNGHHRRQVIASDLIIRHPYALTLFEDSVYWTDRATRRVMRANKWHGGNQSVVM YNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLLSSQGPHFYSCVCPSGWSLSPDLLNC LRDDQPFLITVRQHIIFGISLNPEVKSNDAMVPIAGIQNGLDVEFDDAEQYIYWVENPGE IHRVKTDGTNRTVFASISMVGPSMNLALDWISRNLYSTNPRTQSIEVLTLHGDIRYRKTL IANDGTALGVGFPIGITVDPARGKLYWSDQGTDSGVPAKIASANMDGTSVKTLFTGNLEH LECVTLDIEEQKLYWAVTGRGVIERGNVDGTDRMILVHQLSHPWGIAVHDSFLYYTDEQY EVIERVDKATGANKIVLRDNVPNLRGLQVYHRRNAAESSNGCSNNMNACQQICLPVPGGL FSCACATGFKLNPDNRSCSPYNSFIVVSMLSAIRGFSLELSDHSETMVPVAGQGRNALHV DVDVSSGFIYWCDFSSSVASDNAIRRIKPDGSSLMNIVTHGIGENGVRGIAVDWVAGNLY FTNAFVSETLIEVLRINTTYRRVLLKVTVDMPRHIVVDPKNRYLFWADYGQRPKIERSFL DCTNRTVLVSEGIVTPRGLAVDRSDGYVYWVDDSLDIIARIRINGENSEVIRYGSRYPTP YGITVFENSIIWVDRNLKKIFQASKEPENTEPPTVIRDNINWLRDVTIFDKQVQPRSPAE VNNNPCLENNGGCSHLCFALPGLHTPKCDCAFGTLQSDGKNCAISTENFLIFALSNSLRS LHLDPENHSPPFQTINVERTVMSLDYDSVSDRIYFTQNLASGVGQISYATLSSGIHTPTV IASGIGTADGIAFDWITRRIYYSDYLNQMINSMAEDGSNRTVIARVPKPRAIVLDPCQGY LYWADWDTHAKIERATLGGNFRVPIVNSSLVMPSGLTLDYEEDLLYWVDASLQRIERSTL TGVDREVIVNAAVHAFGLTLYGQYIYWTDLYTQRIYRANKYDGSGQIAMTTNLLSQPRGI NTVVKNQKQQCNNPCEQFNGGCSHICAPGPNGAECQCPHEGNWYLANNRKHCIVDNGERC GASSFTCSNGRCISEEWKCDNDNDCGDGSDEMESVCALHTCSPTAFTCANGRCVQYSYRC DYYNDCGDGSDEAGCLFRDCNATTEFMCNNRRCIPREFICNGVDNCHDNNTSDEKNCPDR TCQSGYTKCHNSNICIPRVYLCDGDNDCGDNSDENPTYCTTHTCSSSEFQCASGRCIPQH WYCDQETDCFDASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDGDNDCGDMSDEDKR HQCQNQNCSDSEFLCVNDRPPDRRCIPQSWVCDGDVDCTDGYDENQNCTRRTCSENEFTC GYGLCIPKIFRCDRHNDCGDYSDERGCLYQTCQQNQFTCQNGRCISKTFVCDEDNDCGDG SDELMHLCHTPEPTCPPHEFKCDNGRCIEMMKLCNHLDDCLDNSDEKGCGINECHDPSIS GCDHNCTDTLTSFYCSCRPGYKLMSDKRTCVDIDECTEMPFVCSQKCENVIGSYICKCAP GYLREPDGKTCRONSNIEPYLIFSNRYYLRNLTIDGYFYSLILEGLDNVVALDFDRVEKR LYWIDTQRQVIERMFLNKTNKETIINHRLPAAESLAVDWVSRKLYWLDARLDGLFVSDLN GGHRRMLAQHCVDANNTFCFDNPRGLALHPQYGYLYWADWGHRAYIGRVGMDGTNKSVII STKLEWPNGITIDYTNDLLYWADAHLGYIEYSDLEGHHRHTVYDGALPHPFAITIFEDTI YWTDWNTRTVEKGNKYDGSNRQTLVNTTHRPFDIHVYHPYRQPIVSNPCGTNNGGCSHLC LIKPGGKGFTCECPDDFRTLQLSGSTYCMPMCSSTQFLCANNEKCIPIWWKCDGQKDCSD GSDELALCPQRFCRLGQFQCSDGNCTSPQTLCNAHQNCPDGSDEDRLLCENHHCDSNEWQ CANKRCIPESWQCDTFNDCEDNSDEDSSHCASRTCRPGQFRCANGRCIPQAWKCDVDNDC GDHSDEPIEECMSSAHLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQGCEERTCH PVGDFRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIPSRWICDH YNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSADCLDASDEADCPTRFPDGA YCQATMFECKNHVCIPPYWKCDGDDDCGDGSDEELHLCLDVPCNSPNRFRCDNNRCIYSH EVCNGVDDCGDGTDETEEHCRKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDEL GCNKGKERTCAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDINECEQFGTCPQH CRNTKGSYECVCADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKYNLSSERFSEYLQD EEYIQAVDYDWDPKDIGLSVVYYTVRGEGSRFGAIKRAYIPNFESGRNNLVQEVDLKLKY VMQPDGIAVDWVGRHIYWSDVKNKRIEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMF WTDWGKEPKIESAWMNGEDRNILVFEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYD GTDRRVIAKEAMNPYSLDIFEDQLYWISKEKGEVWKONKFGQGKKEKTLVVNPWLTQVRI FHQLRYNKSVPNLCKQICSHLCLLRPGGYSCACPQGSSFIEGSTTECDAAIELPINLPPP CRCMHGGNCYFDETDLPKCKCPSGYTGKYCEMAFSKGISPGTTAVAVLLTILLIVVIGAL AIAGFFHYRRTGSLLPALPKLPSLSSLVKPSENGNGVTFRSGADLNMDIGVSGFGPETAI DRSMAMSEDFVMEMGKQPIIFENPMYSARDSAVKVVQPIQVTVSENVDNKNYGSPINPSE IVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPIYAQMENEQKESVAATPPPSPSLP AKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSEV.

[0078] As used herein, target sequence refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a gene of interest for example a CD320 gene or an LRP2 gene, including mRNA that is a product of RNA processing of a primary transcription product.

[0079] As used herein, the term strand comprising a sequence refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature.

[0080] G, C, A and U each generally stand for a nucleotide that contains guanine, cytosine, adenine, and uracil as a base, respectively. T and dT are used interchangeably herein and refer to a deoxyribonucleotide wherein the nucleobase is thymine, e.g., deoxyribothymine, 2-deoxythymidine or thymidine. However, it will be understood that the term ribonucleotide or nucleotide or deoxyribonucleotide can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. The skilled person is well aware that guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base may base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine may be replaced in the nucleotide sequences of the invention by a nucleotide containing, for example, inosine. Sequences comprising such replacement moieties are embodiments of the invention.

[0081] The term siRNA refers to a compound, cocktail, composition or agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via the RISC/AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity, resulting in mRNA degradation and the protein encoded by the mRNA is not produced or is produced at a reduced level as compared to untreated cell. This causes the knockdown effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells. The siRNA modulates, e.g., inhibits, the expression of CD320 in a cell or LRP2 in a cell, e.g., a cell within a subject, such as a mammalian subject.

[0082] In one embodiment, an RNAi agent of the invention includes a single stranded RNA that interacts with a target RNA sequence, e.g., a CD320 or LRP2 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair (bp) short interfering RNAs with characteristic two base 3 overhangs (Bernstein, et al., (2001) Nature 409:363). Initially, the siRNAs may consist of two RNA strands, an antisense (or guide) strand and a sense (or passenger) strand, which form a duplex that varies in length from 10-80 bp in length with or without a 3 nucleotide overhang. A dsRNA can include one or more single-stranded overhang(s) of one or more nucleotides. In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, generally 1 or 2 nucleotides. In another embodiment, the antisense strand of the dsRNA has 1-10 nucleotide overhangs each at the 3 end and the 5 end over the sense strand. In further embodiments, the sense strand of the dsRNA has 1-10 nucleotide overhangs each at the 3 end and the 5 end over the antisense strand.

[0083] The siRNA are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense (guide) strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the invention relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., a CD320 or LRP2 gene. Accordingly, the term siRNA is also used herein to refer to an RNAi as described above.

[0084] In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-80 nucleotides and may be chemically modified to improve metabolic stability and activity; wherein one or multiple pyrimidine nucleotides could be modified as 2-deoxy-2-fluoronucleotides, one or more purine nucleotides could be modified as 2-deoxypurine nucleotides and, moreover, wherein terminal cap modifications could be present at the 3 or 5 ends; particularly by the introduction of one or more 2-deoxythymidine nucleotides, or by the introduction of one or more phosphorothioate groups linking any nucleotides in the sequence but especially at the 3 and 5 end. In addition, a 3-terminal phosphate or vinylphosphonate group could be introduced. Examples of such modifications would include but not be limited to modifications to the ribose moieties of the nucleotides such as: 2-deoxy, 2-deoxyfluoro, 2-methoxy (2-O-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205), and 2-methoxyethyl, wherein it is understood that the stereochemistry of the 2-substituent could be in the ribo- or arabino-orientation. Another modification could be 2-trifluoromethoxy. Other modifications to the ribose moieties could include bridging modifications such that the 2-carbon of the sugar moiety is covalently linked to the 4-carbon of the sugar moiety by a methylene or methoxymethylene group to afford bridged nucleotides described in the art as LNA and (S)-cET, respectively (Corey et al., (2018) Nuc Acid Res 46; 1584-1600). In addition, the sugar moiety could be modified by removal of the bond between carbons C2 and C3 to afford open chain nucleotides analogous to those described in WO 2011/139843 A2. The ribose moiety of the RNA nucleotides could also be replaced by a morpholino group to afford PMO nucleotides. Modifications to the phosphate diester moieties of the nucleotides are also possible and could include but not be limited to replacement of the phosphodiester group by phosphorothioate and thio-phosphoramidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the strand could be modified with 2-deoxynucleotides such as dT and, further, the dT nucleotides could be modified by phosphorothioate groups in place of diphosphate esters. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012) Cell 150:883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150; 883-894.

[0085] In another embodiment, an RNAi for use in the compositions, uses, and methods of the invention is a double-stranded RNA and is referred to herein as a double stranded RNAi agent, double-stranded RNA (dsRNA) molecule, dsRNA agent, or dsRNA. The term dsRNA refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having sense (passenger) and antisense (guide) orientations with respect to a target RNA, i.e., a CD320 gene or LRP2 gene. In some embodiments of the invention, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi.

[0086] In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, as used in this specification, an RNAi agent may include ribonucleotides with chemical modifications (Corey et al., (2018) Nuc Acid Res 46; 1584-1600); an RNAi agent may include substantial modifications at multiple nucleotides or at a single nucleotide. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by RNAi agent for the purposes of this specification and claims. Examples of such modifications would include but not be limited to modifications to the ribose moieties of the nucleotides such as: 2-deoxy, 2-deoxyfluoro, 2-methoxy (2-O-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205), and 2-methoxyethyl, wherein it is understood that the stereochemistry of the 2-substituent could be in the ribo- or arabino-orientation. Another modification could be 2-trifluoromethoxy. Other modifications to the ribose moieties could include bridging modifications such that the 2-carbon of the sugar moiety is covalently linked to the 4-carbon of the sugar moiety by a methylene or methoxymethylene group to afford bridged nucleotides described in the art as LNA and (S)-cET, respectively (Corey et al., (2018) Nuc Acid Res 46; 1584-1600). In addition, the sugar moiety could be modified by removal of the bond between carbons C2 and C3 to afford open chain nucleotides analogous to those described in WO 2011/139843 A2. The ribose moiety of the RNA nucleotides could also be replaced by a morpholino group to afford PMO nucleotides. Modifications to the phosphate diester moieties of the nucleotides are also possible and could include but not be limited to replacement of the phosphodiester group by phosphorothioate and thio-phosphoramidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the sense and antisense strands could be modified with 2-deoxynucleotides such as dT and, further, the dT nucleotides could be modified by phosphorothioate groups in place of diphosphate esters (FIG. 19).

[0087] Chemical modifications to the ribonucleotides could be made at any individual or combination of nucleotides in the antisense and sense strands. In some cases, all the nucleotides in either the antisense or sense strand, or in both the antisense and sense strands are chemically modified (Allerson et al., (2005) J Med Chem 48, 901-904). In other cases, only some of the nucleotides in the antisense or sense strand, or in both the antisense and sense strands are chemically modified (Chiu et al., (2003) RNA 9, 1034-1048). In yet other cases, the modifications could follow a pattern of alternating 2-methoxy and 2-fluoro modifications to either or both strands of the siRNA and sometimes the complementary nucleotides of the antisense and sense strands could contain chemical modifications which are not identical, for example, where one member of a complementary nucleotide pair has a 2-methoxy modification and the other member has a 2-fluoro modification (Choung et al. (2006) Biochem Biophys Res Commun 342, 919-927; Hassler et al., (2018) Nucleic Acid Res 46, 2185-2196).

[0088] The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3-end of one strand and the 5-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a hairpin loop. Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3-end of one strand and the 5-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a linker. The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi agent may comprise one or more nucleotide overhangs.

[0089] In one embodiment, an RNAi agent of the invention is a dsRNA of 20-30 nucleotides that interacts with a target RNA sequence, e.g., a CD320 target mRNA sequence or a LRP2 target mRNA sequence, to direct the cleavage of the target RNA.

[0090] The term antisense strand refers to the strand of a double stranded RNAi agent which includes a region that is substantially complementary to a target sequence (e.g., a human CD320 mRNA or a LRP2 mRNA). As used herein, the term region complementary to part of an mRNA encoding CD320 or LRP2 refers to a region on the antisense strand that is substantially complementary to part of a mRNA sequence that codes for either CD320 or LRP2. Where the region of complementarity is not fully complementary to the target sequence, the mismatches are most tolerated in the terminal regions and, if present, are generally in a terminal region or regions, e.g., within 6, 5, 4, 3, or 2 nucleotides of the 5 and/or 3 terminus. For example, substantially complementary can in certain embodiments mean that in a hybridized pair of nucleobase sequences, at least 85% but not all of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.

[0091] The term sense strand, as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.

[0092] As used herein, the term cleavage region refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13.

[0093] As used herein, and unless otherwise indicated, the term complementary, when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions may include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50 C. or 70 C. for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as may be encountered inside an organism, can apply. For example, a complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.

[0094] Sequences can be fully complementary with respect to each when there is base-pairing of the nucleotides of the first nucleotide sequence with the nucleotides of the second nucleotide sequence over the entire length of the first and second nucleotide sequences. However, where a first sequence is referred to as substantially complementary with respect to a second sequence herein, the two sequences can be fully complementary, or they may form one or more, but generally not more than 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as fully complementary for the purposes described herein.

[0095] Complementary sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G: U Wobble or Hoogstein base pairing.

[0096] The terms complementary, fully complementary and substantially complementary herein may be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of a dsRNA and a target sequence, as will be understood from the context of their use.

[0097] As used herein, a polynucleotide that is substantially complementary to at least part of a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding CD320 or an mRNA encoding LRP2) including a 5 UTR, an open reading frame (ORF), or a 3 UTR. For example, a polynucleotide is complementary to at least a part of a CD320 mRNA or LRP2 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding CD320 or LRP2.

[0098] The term inhibiting, as used herein, is used interchangeably with reducing, silencing, downregulating, suppressing and other similar terms, and includes any level of inhibition.

[0099] The phrase inhibiting expression of a CD320, inhibiting expression of a LRP2 as used herein, includes inhibition of expression of any CD320 or LRP2 gene (such as the identified gene from, e.g., a mouse, a rat, a monkey, or a human) as well as variants, (e.g., naturally occurring variants), or mutants of the identified gene. Thus, the CD320 or LRP2 gene may be a wild-type CD320 or LRP2 gene, a mutant CD320 or LRP2 gene, or a transgenic CD320 or LRP2 gene in the context of a genetically manipulated cell, group of cells, or organism.

[0100] Inhibiting expression of a CD320 gene or Inhibiting expression of a LRP2 gene includes any level of inhibition of a CD320 gene or a LRP2 gene, e.g., at least partial suppression of the expression of a CD320 or LRP2 gene, such as an inhibition of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. In a preferred embodiment the inhibition is assessed by expressing the level of CD320 or LRP2 protein in treated cells as a percentage of the level of mRNA in control cells, using the following formula: [0101] Normalized protein level for treated cells/Normalized protein level for control cells. The control cells are the negative control siRNA. Normalized means the protein level is normalized to the level of a housekeeping protein.

[0102] The expression of a CD320 or LRP2 gene may be assessed based on the level of any variable associated with CD320 or LRP2 gene expression, e.g., CD320 or LRP2 mRNA level, CD320 or LRP2 protein level. Inhibition may be assessed by a decrease in an absolute or relative level of one or more of these variables compared with a control level. The control level may be any type of control level that is utilized in the art, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or sample that is untreated or treated with a control (such as, e.g., buffer only control or inactive agent control).

[0103] Contacting a cell with a RNAi agent, either ds or ss as used herein, includes contacting a cell by any possible means whether in vivo or in vitro. Contacting a cell with a RNAi agent includes contacting a cell in vitro with the RNAi agent or contacting a cell in vivo with the RNAi agent. The contacting may be done directly or indirectly. Thus, for example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell.

[0104] A patient or subject, as used herein, is intended to include either a human or non-human animal, preferably a mammal, e.g., a monkey. Most preferably, the subject or patient is a human.

[0105] A CD320-associated disease, as used herein, is intended to include any disease associated with a perturbation of the CD320 gene, or protein, polymorphisms, single nucleotide polymorphisms (SNPs) as well as epigenetic modifications of the CD320 gene. Such a disease may be caused, for example, by excess production of the CD320 protein, by CD320 gene mutations, by abnormal cleavage of the CD320 protein, by abnormal folding of the CD320 protein, by abnormal interactions between CD320 itself or with other proteins or other endogenous or exogenous substances. For example, cancer may be a CD320-associated disease. The degree of inhibition of protein expression may be measured by western blotting.

[0106] A LRP2-associated disease, as used herein, is intended to include any disease associated with a perturbation of the LRP2 gene, protein, polymorphisms, SNPs as well as epigenetic modifications of the CD320 gene. Such a disease may be caused, for example, by excess production of the LRP2 protein, by LRP2 gene mutations, by abnormal cleavage of the LRP2 protein, by abnormal folding of the LRP2 protein, by abnormal interactions between LRP2 molecules and other proteins or other endogenous or exogenous substances. For example, cancer may be a LRP2-associated disease. The degree of inhibition of protein expression may be measured by western blotting.

[0107] Therapeutically effective amount, as used herein, is intended to include the amount of an RNAi agent that, when administered to a cell or a patient for treating a CD320 associated disease or a LRP2 associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease or by preferentially causing the death of a disease cell as compared to a non-disease cell). The therapeutically effective amount may vary depending on the RNAi agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes mediated by CD320 or LRP2 expression, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

[0108] Prophylactically effective amount, as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject who does not yet experience or display symptoms of a CD320 associated disease or a LRP2 associated disease, but who may be predisposed to the disease, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The prophylactically effective amount may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

[0109] A therapeutically-effective amount or prophylactically effective amount also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. RNAi agents employed in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.

Pharmaceutical Compositions

[0110] The methods described herein include administration of a LRP2 inhibiting composition and/or a CD320 inhibiting composition, e.g., a first siRNA targeting a CD320 gene and/or a second siRNA targeting a LRP2 gene. In some embodiments, the LRP2 inhibiting composition and/or the CD320 inhibiting composition is a pharmaceutical composition.

[0111] The methods described herein also include administration of one or multiple LRP2 inhibiting compositions and/or one or multiple CD320 inhibiting compositions, e.g., one or more siRNAs targeting a CD320 gene and/or one or more siRNAs targeting an LRP2 gene. It is understood that such compositions could be chemically modified in a variety of ways and that such modifications need not be identical in compositional mixtures. In some embodiments, the LRP2 inhibiting composition and/or the CD320 inhibiting composition is a pharmaceutical composition.

[0112] The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical, pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intraparenchymal, intrathecal or intraventricular, administration.

[0113] The compositions can be delivered in a manner to target a particular tissue, such as the lung cells or breast cells or brain cells or bladder cells or uterine cells or cervix cells or prostate cells. Pharmaceutical compositions can be delivered by injection directly into the brain. The injection can be by stereotactic injection into a particular region of the brain (e.g., the substantia nigra, cortex, hippocampus, striatum, or globus pallidus), or the dsRNA can be delivered into multiple regions of the central nervous system (e.g., into multiple regions of the brain, and/or into the spinal cord). The dsRNA can also be delivered into diffuse regions of the brain (e.g., diffuse delivery to the cortex of the brain). In general siRNAs are administered 1) by intratumoral injection, 2) by systemic injection, 3) by slow release from an implanted polymer. Other tissue specificity could be achieved by antibody or small molecule conjugation, or by a tissue-specific delivery device (e.g., a catheter can be used to deliver to the bladder).

[0114] In one embodiment, an RNAi targeting either LRP2 or the CD320 can be delivered by way of a cannula or other delivery device having one end implanted in a tissue. The cannula can be connected to a reservoir of the RNAi composition. The flow or delivery can be mediated by a pump, e.g., an osmotic pump or minipump. In one embodiment, a pump and reservoir are implanted in an area distant from the tissue, e.g., in the abdomen, and delivery is affected by a conduit leading from the pump or reservoir to the site of release.

[0115] Accordingly, in some embodiments, the pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients. The pharmaceutical compositions described herein are formulated for administration to a subject.

[0116] As used herein, a pharmaceutical composition or medicament includes a pharmacologically effective amount of at least one of the described RNAi agents and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical Ingredient (API, therapeutic product, e.g., CD320 RNAi agent or LRP2 RNAi agent) that are intentionally included in the drug delivery system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients can act to a) aid in processing of the drug delivery system during manufacture, b) protect, support, or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and/or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance.

[0117] Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents.

[0118] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The composition, understood to include formulations and drug delivery systems, should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0119] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0120] Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

[0121] The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

Dosage and Timing

[0122] The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the LRP2 inhibiting composition and or the CD320-inhibiting compositions encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein.

[0123] In general, a suitable dose of a pharmaceutical composition of the LRP2 inhibiting composition and/or the CD320-inhibiting composition will be in the range of 0.01 to 300.0 milligrams per kilogram body weight of the recipient per day, generally in the range of 1 to 50 mg per kilogram body weight per day.

[0124] For example, the LRP2 inhibiting composition and/or the CD320-inhibiting composition can be an siRNA composition of one or more siRNAs, and can be administered at, 0.01 mg/kg, 0.05 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.628 mg/kg, 2 mg/kg, 3 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 400 mg/kg per single dose. In another embodiment, the dosage is between 0.15 mg/kg and 0.3 mg/kg. For example, the LRP2 and/or the CD320-inhibiting composition can be administered at a dose of 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, or 0.3 mg/kg. In an embodiment, the LRP2 and/or the CD320-inhibiting composition is administered at a dose of 0.3 mg/kg.

[0125] The pharmaceutical composition may be administered once daily, or once or twice every 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. The dosage unit can be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the LRP2 inhibiting composition and/or the CD320-inhibiting composition over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention.

[0126] In an embodiment, the LRP2-inhibiting composition and/or the CD320-inhibiting composition is dependent upon the tumor cell line, and the dosage is 0.3 mg/kg, and wherein the dose is administered once every 21 days. In another embodiment, the effective amount is 0.3 mg/kg and the effective amount is administered once every 21 days via a 70 minute infusion of 1 mL/min for 15 minutes followed by 3 mL/min for 55 minutes. In another embodiment, the effective amount is 0.3 mg/kg and the effective amount is administered at two doses every 21-28 days via a 60 minute infusion of 3.3 mL/min, or via a 70 minute infusion of 1.1 mL/min for 15 minutes followed by 3.3 mL/min for 55 minutes

[0127] A dosage of a LRP2-inhibiting composition and/or the CD320-inhibiting composition can be adjusted for treatment

[0128] A LRP2-inhibiting composition and/or the CD320-inhibiting composition can be administered in combination with other known agents effective in treatment of pathological processes mediated by target gene expression.

[0129] In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.

[0130] In embodiments of the pharmaceutical compositions described herein, the RNAi (e.g., dsRNA) is administered with a buffer solution. In embodiments, the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof. In embodiments, the buffer solution is phosphate buffered saline (PBS).

[0131] In embodiments of the pharmaceutical compositions described herein, the composition is administered intravenously.

[0132] In embodiments of the pharmaceutical compositions described herein, the composition is administered subcutaneously.

[0133] In certain embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a lipid formulation. In embodiments, the composition is administered intravenously.

[0134] In some embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a cationic polyamine formulation or nanoparticle (e.g., JetPEI). In some embodiments, the composition is administered intravenously.

[0135] In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.

[0136] In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 or CD320, is administered with a non-RNAi therapeutic agent, such as an agent known to treat a cancer such as lung cancer. In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 and/or CD320, is administered along with a non-RNAi therapeutic regimen, such as radiation, chemotherapy, immunotherapy, photodynamic therapy or a combination thereof.

[0137] In an aspect provided herein is a method of inhibiting LRP2 and/or CD320 expression in a cell, the method comprising: (a) introducing into the cell an RNAi agent (e.g., a dsRNA) described herein and (b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of an LRP2 gene and/or CD320 gene, thereby inhibiting expression of the LRP2 gene and/or CD320 gene in the cell.

[0138] In an aspect provided herein is a method for reducing or inhibiting the expression of LRP2 gene and/or CD320 genes in a cell. The method includes: (a) introducing into the cell one or more complimentary double-stranded ribonucleic acid (dsRNA) molecules, in which one sequence is designated the sense strand and the other sequence the anti-sense strand, and wherein the anti-sense strand has significant complementarity to a portion of mRNA encoding for LRP2 or CD320. The complimentary region is 15-30 nucleotides in length, and generally 19-24 nucleotides in length, and the dsRNA, upon entering a cell expressing LRP2 and/or CD320, inhibits the expression of the LRP2 protein and/or CD320 protein by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more; (b) single or repeated treatment of the cell with dsRNAs, as described in part (a), so as to maintain the inhibition of LRP2 and/or CD320 protein expression over a desired period of time by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more.

[0139] In embodiments of the foregoing methods of inhibiting LRP2 and/or CD320 expression in a cell, the cell is treated ex vivo, in vitro, or in vivo. In embodiments, the cell is a melanoma, glioblastoma, lung carcinoma, triple negative breast carcinoma, renal carcinoma, pancreatic carcinoma, hepatocellular carcinoma, ovarian carcinoma and prostate carcinoma.

[0140] In some embodiments, the cell is present in a subject in need of treatment, prevention and/or management of a CD320-associated disease or a LRP2-associated disease.

[0141] In embodiments, the expression of LRP2 and/or CD320 is inhibited by at least 30%.

[0142] In embodiments, the RNAi (e.g., dsRNA) has an IC.sub.50 in the range of 0.01-50 nM.

[0143] In embodiments, the RNAi (e.g., dsRNA) has an IC.sub.50 in the range of 0.01-1 nM.

[0144] In certain embodiments, the cell is a mammalian cell (e.g., a human, non-human primate, or rodent cell).

[0145] In one embodiment, the cell is treated ex vivo, in vitro, or in vivo (e.g., the cell is present in a subject (e.g., a patient in need of treatment, prevention and/or management of a disorder related to LRP2 and/or CD320 expression).

[0146] In one embodiment, the subject is a mammal (e.g., a human) at risk, or diagnosed with a proliferation disorder.

[0147] In embodiments, the RNAi (e.g., dsRNA) is formulated as an lipid nanoparticle (LNP) polyplex (polyamine) formulation.

[0148] In embodiments, RNAi (e.g., dsRNA) is administered at a dose of 0.05001-500.01 mg/kg.

[0149] In embodiments, the RNAi (e.g., dsRNA) is administered at a concentration of 0.01 mg/kg-50.1 mg/kg bodyweight of the subject.

[0150] In embodiments, the RNAi (e.g., dsRNA) is formulated as an LNP formulation and is administered at a dose of 0.050.1-50.5 mg/kg.

[0151] In embodiments, the RNAi (e.g., dsRNA) has an IC.sub.50 in the range of 0.01-10 nM.

[0152] In embodiments, the RNAi (e.g., dsRNA) or composition comprising the RNAi is administered according to a dosing regimen. In embodiments, the RNAi (e.g., dsRNA) or composition comprising the RNAi is administered as a single dose or at multiple doses, e.g., according to a dosing regimen.

[0153] The term sample, as used herein, includes a collection of fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from a tumor. In preferred embodiments, a sample derived from a subject refers to blood or plasma drawn from the subject. In further embodiments, a sample derived from a subject refers to tissue biopsy derived from the subject.

[0154] In one embodiment, an RNAi (e.g., a dsRNA) featured herein includes a first sequence of a dsRNA that is selected from the group consisting of the sense sequences of Table 1 and a second sequence that is selected from the group consisting of the corresponding antisense sequences of Table 1. It is understood that the suffix A (e.g., OSC17A) represents the antisense strand whereas the suffix S (e.g., OSC17S) represents the sense strand. In those instances when we refer to an siRNA with no suffix (e.g., OSC17), we mean that to indicate the dsRNA comprised of the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC17S).

[0155] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting CD320, upon contact with a cell expressing CD320, inhibits the expression of a CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting CD320 is formulated in a stable nucleic acid lipid particle (SNALP).

[0156] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting LRP2, upon contact with a cell expressing LRP2, inhibits the expression of a LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting LRP2 is formulated in a stable nucleic acid lipid particle (SNALP).

[0157] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting CD320, upon contact with a cell expressing CD320, inhibits the expression of a CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting CD320 is formulated as a complex, which may exist as a nanoparticle, with a cationic polyamine.

[0158] In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting LRP2, upon contact with a cell expressing LRP2, inhibits the expression of a LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting LRP2 is formulated as a complex, which may exist as a nanoparticle, with a cationic polyamine.

[0159] Referring now to Table 1-DNA sequences are illustrated, which are subsequently transcribed into shRNA, which hence targets the CD320 or LRP2 mRNA for destruction in the cell. shRNA sequences used in lentiviral vectors illustrates the sequences that were used to target the CD320 sequence coding for the CD320 protein and the LRP2 sequence coding for the LRP2 protein. The Each vector that carried a shRNA coding sequence also contained a unique drug resistance gene which would allow for selecting those cells that had taken up the shRNA as those cells that had not taken up the shRNA having the unique drug resistance gene would not survive. On day 2, drug selection was started. On day 3, the cells were harvested and plated in a new dish. Only the cells with a drug resistance gene, i.e., those cells that had taken up shRNA virus particles would survive this re-plating procedure. From day 4 on, each culture was closely observed for cell growth. The cells that were infected with the irrelevant control shRNA kept on growing as expected (since the shRNA was essentially a non-functional shRNA)data not shown. The results for the cell lines that took up the CD320+LRP2 shRNAs are shown in Table 1.

TABLE-US-00012 TABLE1 Anti-Sense Location Name Target SenseSequence Sequence inDNA shScramble non-targeting CCTAAGGTTAAGTC CGAGGGCGACTTAAC N/A control GCCCTCG CTTAGG (SEQIDNO.941) (SEQIDNO.942) shCD320-#27 CD320 CCCTCAGAGACCTG AAGAGCTCAGGTCTC 1006- (NM_016579.3) AGCTCTT TGAGGG 1026 (SEQIDNO.943) (SEQIDNO.944) shLRP2-#89 LRP2 CCTGTAATAAACAC AAGAGTAGTGTTTAT 2800- (NM_004525.2) TACTCTT TACAGG 2820 (SEQIDNO.945) (SEQIDNO.946)

[0160] The preliminary studies show that cancer cells are selectively killed by CD320 and LRP2 knockdown, while normal cells remain unaffected (Table 2).

[0161] Table 2 shows the effect of simultaneous knockdown of CD320 and LRP2 on cell viability.

TABLE-US-00013 TABLE 2 Outcome of CD320/LRP2 knockdown Cell arrest/death Alive Cancer (Lung) HCC15 H157 H358 H1999 Non-cancer Normal fibroblast LDLR mutant fibroblast

[0162] Additional cancer cell lines were also treated with the compounds described herein to determine whether cancer cell lines were more susceptible to growth inhibition and toxicity as compared to non-cancer cells of the same origin. Cell lines from skin, prostate, and brain cancers were screened similarly to the experimental outline in FIG. 1. Table 3 summarizes the effects of simultaneous knockdown of CD320 and LRP2 in cancer and normal cells.

TABLE-US-00014 TABLE 3 shCD320 + Cell shSCR shCD320 shLRP2 shLRP2 Comments Normal cells GM05659 +++ +++ +++ +++ no effect of knockdown GM00701 +++ ++ +++ +++ cells grow very slow; hard to determine if any affect of knockdown SAEC pending Lung cells HCC15 +++ + + + cells strongly affected by knockdown H157 +++ + ++ + senescent phenotype H358 +++ ++ ++ ++ morphology changes; cells rounded H1993 +++ ++ ++ + cells rounded; morphology change Melanoma Cells MDA-MB-4353 +++ ++ + + morphology change; cells strongly affected by double knockdown Prostate cells LncAP +++ ++ ++ + cells rounded; morphology change PC3 +++ +++ ++ +++ cells minimally to not affected by knockdown DU-145 +++ ++ + ++ cells modestly affected by knockdown Glioblastoma A172 +++ + + 0 cells strongly affected by knockdown U251MG +++ + ++ 0 cells strongly affected by knockdown U343 +++ +++ ++ +++ cells modestly affected by LRP2 knockdown T98G +++ +++ ++ ++ cells slightly affected by knockdown +++ cells unaffected compared to shSCR (control) ++ cells modestly affected compared to shSCR (control) + cells significantly affected compared to shSCR (control) 0 vast majority of cells killed compared to shSCR (control)

[0163] The screening results showed that lung, prostate, skin, and brain cancer cell lines were growth-inhibited or killed by the simultaneous knockdown (double knockdown) of CD320 and LRP2, while non-cancerous cells were unaffected.

[0164] Referring now to FIG. 2, representative pictures of the cells were taken to record their phenotypes after the double knockdown of CD320 and LRP2 and to illustrate the sensitivity of cancer cell lines to knockdown of the expression of CD320 and LRP2 proteins.

[0165] Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentiviruses expressing shRNAs to control sequences or to shCD320 and shLRP2 as described in FIG. 1. The cells were grown as described in FIG. 1. On the ninth day after transfection with the lentiviruses, pictures of the cells were taken. The solid line ovals indicate healthy growth of normal fibroblast infected with shRNAs to CD320 and LRP2. The broken line ovals indicate unhealthy dying cells of cancer cell lines infected with shRNAs to CD320 and LRP2.

[0166] These results support use of the compounds as therapeutics based upon decreasing expression of CD320 and LRP2 protein preferentially resulting in detrimental effects in cancer cells as compared to non-cancer cells. The original experiments were conducted using shRNAs delivered by lentiviral vectors. Short inhibitory RNAs (siRNAs), having a sequence complimentary to a portion of the CD320 protein and/or the LRP2 protein were designed. The siRNAs can be chemically modified to increase their stability and potency and reduce their immunogenicity, and multiple platforms exist for their delivery in clinical applications.

[0167] siRNA sequences that efficiently knock down the protein levels of LRP2 and/or CD320 were designed and identified. Table 4 is a list of siRNA sequences complementary to mRNA for CD320 or LRP2 that were tested for their ability to knock down CD320 or LRP2 protein, respectively (see FIG. 3, FIG. 4, FIG. 5, FIG. 12, and FIG. 15).

TABLE-US-00015 TABLE4 Nucleotide ID PassengerSequence Target Size startsite Location OSS1 CCUAAGGUUAAGUCGCCCUCG none 21 N/A N/A (SEQIDNO.947) OSS2 UGGUUUACAUGUUGUGUGA none 19 N/A N/A (SEQIDNO.948) OSL231 GGGCUCUAGGUUUGGUGCUAU LRP2 25 12537 CDS CAAA(SEQIDNO.949) NM_004525.2 OSL245 GGACUGAUAGGAGAGU LRP2 25 12995 CDS CAUUGCAAA(SEQIDNO.950) NM_004525.2 OSL47 CCUGUAAUAAACACUACUCUU LRP2 21 2800 CDS (SEQIDNO.951) NM_004525.2 OSL104 CCUUCUAUGAACCUGGCCUUA LRP2 21 5677 CDS (SEQIDNO.952) NM_004525.2 OSL90 GUGAUUUGAUUAUACGGCA LRP2 19 5126 CDS (SEQIDNO.953) NM_004525.2 OSL119 CCUCAAAUGGCUGUAGCAA LRP2 19 6266 CDS (SEQIDNO.954) NM_004525.2 OSC17 GAACUGACAAGAAACUGCGCAACUG CD320 25 422 CDS (SEQIDNO.955) NM_016579.3 OSC47 CCCUCAGAGACCUGAGCUCUU CD320 21 1006 3'-UTR (SEQIDNO.956) NM_016579.3

[0168] The list of all potential siRNA sequences is quite large. We have identified 340 potential SIRNA sequences to LRP2 and 59 potential siRNA sequences to CD320. (See Table 5 and Table 6 for the complete list and Table 5A and Table 6A identify the target position and sequence that is complementary for each antisense sequence identified). In addition, chemical modifications can be made to these siRNA sequences to improve their stability and reduce their off-target effects. siRNA molecules are vulnerable to metabolic degradation, for example by RNase or DNase enzymes. Chemical modification of siRNA molecules by incorporation of one or more unnatural, that is, manmade, nucleotides within the sequence can render siRNAs resistant to such metabolic degradation and increase their biological half-life in the cell or in plasma. Moreover, the inclusion of manmade nucleotides at strategic locations within the siRNA sequence can decrease the immunogenicity of the siRNA and improve the selectivity for the guide strand over the passenger strand. Modified siRNA molecules may incorporate manmade nucleotides of a single type or may include multiple manmade nucleotides of different types. Manmade nucleotides may include, but are not limited to, those which contain chemical modifications to the ribose moiety or to the phosphate moieties (FIG. 19 and Table 7). Examples of manmade nucleotides include, but are not limited to, the structures shown in the Table 7. Moreover, modification of multiple structural elements may be combined. In addition, modification may be made to the nucleobase B, which, in addition to the natural RNA nucleobases (G, C, A, U), may include unnatural bases, such as those containing a sulfur atom (e.g., thiouracil).

TABLE-US-00016 TABLE 7 Nucleotide modifications corresponding to FIG. 19A B Designation.sup.a Y X Z R R (nucleobase) [2fN] O O O F H G, C, A, U, other 2-FANA O O O H F G, C, A, U, other [mN] O O O OMe H G, C, A, U, other 2-MOE O O O CH.sub.2CH.sub.2OMe H G, C, A, U, other 2-EA O O O CH.sub.2CH.sub.2NH.sub.2 H G, C, A, U, other 2-DMEA O O O CH.sub.2CH.sub.2NMe.sub.2 H G, C, A, U, other 2-DMAP O O O CH.sub.2CH.sub.2CH.sub.2NMe.sub.2 H G, C, A, U, other * as in N1*N2 O S O OH H G, C, A, U, other ** as in N1**N2 S S O OH H G, C, A, U, other 2-deoxy O O O H H G, C, A, U, other 4-S O O S H H G, C, A, U, other F-SRNA O O S F H G, C, A, U, other Me-SRNA O O S OMe H G, C, A, U, other 4-S-FANA O O S H F G, C, A, U, other .sup.aN designates an arbitrary ribonucleotide or deoxyribonucleotide or analogs thereof.

[0169] In some embodiments, chemical modification is made to the phosphodiester group which covalently connects two nucleotides, such that, for example, one or two oxygen atoms in that group are substituted with sulfur atoms, as indicated by a single or double asterisk between two nucleotides to represent the replacement of one or two oxygen atoms with sulfur in the phosphodiester (Table 7 and FIG. 19A). In some embodiments, the siRNA sequences may include other manmade nucleotides wherein further structural modifications have been made to the ribose moiety, such as the addition of bridging atoms that covalently link carbons 2 and 5 of the ribose moiety (FIG. 19B-C) or positions 1 and 2 of the ribose moiety (FIG. 19D), or alternatively, changes to the size of the sugar ring in a given nucleotide, for example, deletion of the bond between carbons 2 and 3 of the ribose moiety (FIG. 19E), or increasing the size of the sugar ring from five to six atoms (FIG. 19F-G).

TABLE-US-00017 TABLE5 CD320 OSID AntisenseStrand(5TO3) OSID SenseStrand(5[TO3) OSC1A UCUUAUCCCUGCGCACGCGCA[dT][dT](SEQ OSC1S UGCGCGUGCGCAGGGAUAAGA[dT][dT] IDNO1) (SEQIDNO:94) OSC2A UCUCUUAUCCCUGCGCACGCG[dT][dT](SEQ OSC2S CGCGUGCGCAGGGAUAAGAGA[dT][dT] IDNO2) (SEQIDNO:95) OSC3A AUGCUGUCCCCACAGCGGCGC[dT][dT](SEQ OSC3S GCGCCGCUGUGGGGACAGCAU[dT][dT] IDNO3) (SEQIDNO:96) OSC4A AUCCAACCGCCGCUCAUGCUG[dT][dT](SEQ OSC4S CAGCAUGAGCGGCGGUUGGAU[dT][dT] IDNO4) (SEQIDNO:97) OSC5A UGGAAAGCGGGCUCGCGGCGG[dT][dT](SEQ OSC5S CCGCCGCGAGCCCGCUUUCCA[dT][dT] IDNO5) (SEQIDNO:98) OSC6A AACUUGGUGGGUGGGCACGAG[dT][dT](SEQ OSC6S CUCGUGCCCACCCACCAAGUU[dT][dT] IDNO6) (SEQIDNO:99) OSC7A UGGAACUUGGUGGGUGGGCAC[dT][dT](SEQ OSC7S GUGCCCACCCACCAAGUUCCA[dT][dT] IDNO7) (SEQIDNO:100) OSC8A ACUGGAACUUGGUGGGUGGGC[dT][dT](SEQ OSC8S GCCCACCCACCAAGUUCCAGU[dT][dT] IDNO8) (SEQIDNO:101) OSC9A UAAGCCACUGGUGCGGCACUG[dT][dT](SEQ OSC9S CAGUGCCGCACCAGUGGCUUA[dT][dT] IDNO9) (SEQIDNO:102) OSC10A ACGCAUAAGCCACUGGUGCGG[dT][dT](SEQ OSC10S CCGCACCAGUGGCUUAUGCGU[dT][dT] IDNO10) (SEQIDNO:103) OSC11A UCCAAGUCCCUGUCGCAGCGC[dT][dT](SEQ OSC11S GCGCUGCGACAGGGACUUGGA[dT][dT] IDNO11) (SEQIDNO:104) OSC12A UCCUCAUCGCUGCCAUCGCUG[dT][dT](SEQ OSC12S CAGCGAUGGCAGCGAUGAGGA[dT][dT] IDNO12) (SEQIDNO:105) OSC13A UCACUGACGCCGGUGCAGGGG[dT][dT](SEQ OSC13S CCCCUGCACCGGCGUCAGUGA[dT][dT] IDNO13) (SEQIDNO:106) OSC14A UUGUCAGUUCCCCCAGAGCAG[dT][dT](SEQ OSC14S CUGCUCUGGGGGAACUGACAA[dT][dT] IDNO14) (SEQIDNO:107) OSC15A UUCUUGUCAGUUCCCCCAGAG[dT][dT](SEQ OSC15S CUCUGGGGGAACUGACAAGAA[dT][dT] IDNO15) (SEQIDNO:108) OSC16A AGUUUCUUGUCAGUUCCCCCA[dT][dT](SEQ OSC16S UGGGGGAACUGACAAGAAACU[dT][dT] IDNO16) (SEQIDNO:109) OSC17A- CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] OSC17S- GAACUGACAAGAAACUGCGCAACUG 1 (SEQIDNO17) 1 [dT][dT](SEQIDNO:110) OSC17A- CAGUUGCGCAGUUUCUUGUCAGUUC[dT]*[dT] OSC17S- GAACUGACAAGAAACUGCGCAACUG[dT]* 2 (SEQIDNO18) 2 [dT](SEQIDNO:111) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 3 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 3 [mA][mA][mG][mA][mA][mA][mC][mU] [mU][mC][mA][mG][mU][mU][mC][dT]*[dT] [mG][mC][mG][mC][mA][mA][mC][mU][mG] (SEQIDNO19) [dT]*[dT](SEQIDNO:112) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 4 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 4 [mA][mA][mG][mA][mA][mA][mC][mU] [mU][mC][mA][mG][mU][mU][mC][dT]*[dT] [mG][mC][mG][mC][mA][mA][mC][mU][mG] (SEQIDNO20) (SEQIDNO:113) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 5 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 5 [mA][mA][mG][mA][mA][mA][mC][mU] [mU][mC][mA][mG][mU][mU][mC](SEQID [mG][mC][mG][mC][mA][mA][mC][mU][mG] NO21) [dT]*[dT](SEQIDNO:114) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 6 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 6 [mA][mA][mG][mA][mA][mA][mC][mU] [mU][mC][mA][mG][mU][mU][mC](SEQID [mG][mC][mG][mC][mA][mA][mC][mU][mG] NO22) (SEQIDNO:115) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- GAACUGACAAGAAACUGCGCAACUG[dT]* 7 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 7 [dT](SEQIDNO:116) [mU][mC][mA][mG][mU][mU][mC] [dT]*[dT](SEQIDNO23) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 8 [2fG][mC][2fA][mG][2fU][mU][2fU][mC] 8 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [2fU][mU][2fG][mU][2fC][mA][2fG][mU] [2fG][mC][2fG][mC][2fA][mA][2fC][mU] [2fU][mC][dT]*[dT](SEQIDNO24) [2fG][dT]*[[dT](SEQIDNO:117) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 9 [mC][2fA][mG][2fU][mU][2fU][mC] 9 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [2fU][mU][2fG][mU][2fC][mA][2fG][mU] [2fG][mC][2fG][mC][2fA][mA][2fC][mU] [2fU][mC](SEQIDNO25) [2fG][dT]*[dT](SEQIDNO:118) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 10 [mC][2fA][mG][2fU][mU][2fU][mC][2fU] 10 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [mU][2fG][mU][2fC][mA][2fG][mU][2fU] [2fG][mC][2fG][mC][2fA][mA][2fC][mU] [mC][dT]*[dT](SEQIDNO26) [2fG](SEQIDNO:119) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 11 [mC][2fA][mG][2fU][mU][2fU][mC] 11 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [2fU][mU][2fG][mU][2fC][mA][2fG][mU] [2fG][mC][2fG][mC][2fA][mA][2fC][mU] [2fU][mC](SEQIDNO27) [2fG](SEQIDNO:120) OSC17A- [2fC][mA][2fG][mU][2fU][mG][2fC][mG] OSC17S- [mG][2fA][mA][2fC][mU][2fG][mA][2fC] 12 [2fC][mA][2fG][mU][2fU][mU][2fC][mU] 12 [mA][2fA][mG][2fA][mA][2fA][mC][2fU] [2fU][mG][2fU][mC][2fA][mG][2fU][mU] [mG][2fC][mG][2fC][mA][2fA][mC][2fU] [2fC][dT]*[dT](SEQIDNO28) [mG][dT]*[dT](SEQIDNO:121) OSC17A- [2fC][mA][2fG][mU][2fU][mG][2fC][mG] OSC17S- [mG][2fA][mA][2fC][mU][2fG][mA][2fC] 13 [2fC][mA][2fG][mU][2fU][mU][2fC][mU] 13 [mA][2fA][mG][2fA][mA][2fA][mC] [2fU][mG][2fU][mC][2fA][mG][2fU] [2fU][mG][2fC][mG][2fC][mA][2fA][mC] [mU][2fC](SEQIDNO29) [2fU][mG](SEQIDNO:122) OSC17A- [mC][2fA][2fG][2fU][2fU][2fG][2fC][2fG] OSC17S- [2fU][mG][2fA][mC][2fA][mA][2fG][mA] 14 [2fC][2fA][2fG][2fU][2fU][2fU][2fC] 14 [2fA][mA][2fC][mU][2fG][mC][2fG][mC] [2fU][2fU][2fG][2fU][2fC][2fA][2fG] [2fA][mA][2fC][mU][2fG][dT]*[dT] [2fU][2fU][2fC][dT]*[dT](SEQIDNO30) (SEQIDNO:123) OSC17A- [mC][2fA][2fG][2fU][2fU][2fG][2fC] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 15 [2fG][2fC][2fA][2fG][2fU][2fU][2fU] 15 [2fG][mC][2fA][mA][2fC][mU][2fG] [2fC][2fU][2fU][2fG][2fU][2fC][2fA] [dT]*[dT](SEQIDNO:124) [2fG][2fU][2fU][2fC][dT]*[dT] (SEQIDNO31) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 16 [mC][2fA][mG][2fU][mU][2fU][mC][2fU] 16 [2fG][mC][2fA][mA][2fC][mU][2fG] [mU][2fG][mU][2fC][mA][2fG][mU][2fU] [dT]*[dT](SEQIDNO:125) [mC][dT]*[dT](SEQIDNO32) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 17 [2fG][mC][2fA][mG][2fU][mU][2fU][mC] 17 [2fG][mC][2fA][mA][2fC][mU][2fG] [2fU][mU][2fG][mU][2fC][mA][2fG] (SEQIDNO:126) [mU](SEQIDNO33) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 18 [mC][2fA][mG][2fU][mU][2fU][mC] 18 [2fG][mC][2fA][mA][2fC][mU][2fG] [2fU][2fU][2fG][2fU][2fC][2fA][2fG] (SEQIDNO:127) [2fU](SEQIDNO34) OSC18A AUGCAGUCAUCGCUCAGCGUG[dT][dT](SEQ OSC18S CACGCUGAGCGAUGACUGCAU[dT][dT] IDNO35) (SEQIDNO:128) OSC19A AAUGCAGUCAUCGCUCAGCGU[dT][dT](SEQ OSC19S ACGCUGAGCGAUGACUGCAUU[dT][dT] IDNO36) (SEQIDNO:129) OSC20A UGGAAUGCAGUCAUCGCUCAG[dT][dT](SEQ OSC20S CUGAGCGAUGACUGCAUUCCA[dT][dT] IDNO37) (SEQIDNO:130) OSC21A AGUGGAAUGCAGUCAUCGCUC[dT][dT](SEQ OSC21S GAGCGAUGACUGCAUUCCACU[dT][dT] IDNO38) (SEQIDNO:131) OSC22A ACAGUCUGGGUGGCCGUCGCA[dT][dT](SEQ OSC22S UGCGACGGCCACCCAGACUGU[dT][dT] IDNO39) (SEQIDNO:132) OSC23A AUUGGUUCCACAGCCGAGCUC[dT][dT](SEQ OSC23S GAGCUCGGCUGUGGAACCAAU[dT][dT] IDNO40) (SEQIDNO:133) OSC24A UCUCAUUGGUUCCACAGCCGA[dT][dT](SEQ OSC24S UCGGCUGUGGAACCAAUGAGA[dT][dT] IDNO41) (SEQIDNO:134) OSC25A AUCUCAUUGGUUCCACAGCCG[dT][dT](SEQ OSC25S CGGCUGUGGAACCAAUGAGAU[dT][dT] IDNO42) (SEQIDNO:135) OSC26A AGGAUCUCAUUGGUUCCACAG[dT][dT](SEQ OSC26S CUGUGGAACCAAUGAGAUCCU[dT][dT] IDNO43) (SEQIDNO:136) OSC27A UGAGAGAGGUGACACUCUCCA[dT][dT](SEQ OSC27S UGGAGAGUGUCACCUCUCUCA[dT][dT] IDNO44) (SEQIDNO:137) OSC28A UGGUUGUGGCAUUCCUGAGAG[dT][dT] OSC28S CUCUCAGGAAUGCCACAACCA[dT][dT] (SEQIDNO45) (SEQIDNO:138) OSC29A UGGCAUUCCCGACAGAGGGGA[dT][dT](SEQ OSC29S UCCCCUCUGUCGGGAAUGCCA[dT][dT] IDNO46) (SEQIDNO:139) OSC30A AGGAUGUGGCAUUCCCGACAG[dT][dT](SEQ OSC30S CUGUCGGGAAUGCCACAUCCU[dT][dT] IDNO47) (SEQIDNO:140) OSC31A UUCCAGACUGGUCUCCGGCAG[dT][dT](SEQ OSC31S CUGCCGGAGACCAGUCUGGAA[dT][dT] IDNO48) (SEQIDNO:141) OSC32A AUAACCCCAUAGGCAGUUGGG[dT][dT](SEQ OSC32S CCCAACUGCCUAUGGGGUUAU[dT][dT] IDNO49) (SEQIDNO:142) OSC33A UUGCACUGAGCACCGCAGCAG[dT][dT](SEQ OSC33S CUGCUGCGGUGCUCAGUGCAA[dT][dT] IDNO50) (SEQIDNO:143) OSC34A AAAAGGAGGAGGGUGGCGGUG[dT][dT](SEQ OSC34S CACCGCCACCCUCCUCCUUUU[dT][dT] IDNO51) (SEQIDNO:144) OSC35A ACAAAAGGAGGAGGGUGGCGG[dT][dT](SEQ OSC35S CCGCCACCCUCCUCCUUUUGU[dT][dT] IDNO52) (SEQIDNO:145) OSC36A ACCAGUAACCCCAGUGGGCGG[dT][dT](SEQ OSC36S CCGCCCACUGGGGUUACUGGU[dT][dT] IDNO53) (SEQIDNO:146) OSC37A UUCAUGGCCACCAGUAACCCC[dT][dT](SEQ OSC37S GGGGUUACUGGUGGCCAUGAA[dT][dT] IDNO54) (SEQIDNO:147) OSC38A ACUCCUUCAUGGCCACCAGUA[dT][dT](SEQ OSC38S UACUGGUGGCCAUGAAGGAGU[dT][dT] IDNO55) (SEQIDNO:148) OSC39A UUCUGACAGCAGCAGGGACUC[dT][dT](SEQ OSC39S GAGUCCCUGCUGCUGUCAGAA[dT][dT] IDNO56) (SEQIDNO:149) OSC40A UCUGUUCUGACAGCAGCAGGG[dT][dT](SEQ OSC40S GGCUGCUGCUGUCAGAACAGA[dT][dT] IDNO57) (SEQIDNO:150) OSC41A UCUUCUGUUCUGACAGCAGCA[dT][dT](SEQ OSC41S UGCUGCUGUCAGAACAGAAGA[dT][dT] IDNO58) (SEQIDNO:151) OSC42A AGGUCUUCUGUUCUGACAGCA[dT][dT](SEQ OSC42S UGCUGUCAGAACAGAAGACCU[dT][dT] IDNO59) (SEQIDNO:152) OSC43A UUGUCCUCAGGGCAGCGAGGU[dT][dT](SEQ OSC43S ACCUCGCUGCCCUGAGGACAA[dT][dT] IDNO60) (SEQIDNO:153) OSC44A AAGUGCUUGUCCUCAGGGCAG[dT][dT](SEQ OSC44S CUGCCCUGAGGACAAGCACUU[dT][dT] IDNO61) (SEQIDNO:154) OSC45A UACCCAUCCGCAUCACUGCUC[dT][dT](SEQ OSC45S GAGCAGUGAUGCGGAUGGGUA[dT][dT] IDNO62) (SEQIDNO:155) OSC46A UCUCUGAGGGCUGGUGUGCCC[dT][dT](SEQ OSC46S GGGCACACCAGCCCUCAGAGA[dT][dT] IDNO63) (SEQIDNO:156) OSC47A- AAGAGCUCAGGUCUCUGAGGG[dT][dT](SEQ OSC47S- CCCUCAGAGACCUGAGCUCUU[dT][dT] 1 IDNO64) 1 (SEQIDNO:157) OSC47A- AAGAGCUCAGGUCUCUGAGGG[dT]*[dT] OSC47S- CCCUCAGAGACCUGAGCUCUU[dT]*[dT] 2 (SEQIDNO65) 2 (SEQIDNO:158) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 3 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 3 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG][dT]*[dT](SEQIDNO66) [mC][mU][mC][mU][mU][dT]*[dT] (SEQIDNO:159) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 4 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 4 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG][dT]*[dT](SEQIDNO67) [mC][mU][mC][mU][mU] (SEQIDNO:160) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 5 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 5 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG](SEQIDNO68) [mC][mU][mC][mU][mU][dT]*[dT] (SEQIDNO:161) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 6 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 6 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG](SEQIDNO69) [mC][mU][mC][mU][mU] (SEQIDNO:162) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- CCCUCAGAGACCUGAGCUCUU[dT]*[dT] 7 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 7 (SEQIDNO:163) [mG][mG][mG][dT]*[dT](SEQIDNO70) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 8 [mA][2fG][mG][2fU][mC][2fU][mC] 8 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [2fU][mG][2fA][mG][2fG][mG][dT]* [2fC][mU][2fC][mU][2fU][dT]*[dT] [dT](SEQIDNO71) (SEQIDNO:164) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 9 [mA][2fG][mG][2fU][mC][2fU] 9 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [mC][2fU][mG][2fA][mG][2fG] [2fC][mU][2fC][mU][2fU][dT]*[dT] [mG](SEQIDNO72) (SEQIDNO:165) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 10 [mA][2fG][mG][2fU][mC][2fU][mC][2fU] 10 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [mG][2fA][mG][2fG][mG][dT]*[dT] [2fC][mU][2fC][mU][2fU] (SEQIDNO73) (SEQIDNO:166) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG] 11 [mA][2fG][mG][2fU][mC][2fU][mC][2fU] 11 [mA][2fG[mA][2fC][mC][2fU][mG][2fA] [mG][2fA][mG][2fG][mG] [mG][2fC][mU][2fC][mU][2fU] (SEQIDNO74) (SEQIDNO:167) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC] OSC47S- [mC][2fC][mC][2fU][mC][2fA][mG][2fA] 12 [2fA][mG][2fG][mU][2fC][mU][2fC] 12 [mG][2fA][mC][2fC][mU][2fG][mA][2fG] [mU][2fG][mA][2fG][mG][2fG][dT]*[dT] [mC][2fU][mC][2fU][mU][dT][dT]* (SEQIDNO75) (SEQIDNO:168) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 13 [2fA][mG][2fG][mU][2fC][mU][2fC] 13 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [mU][2fG][mA][2fG][mG][2fG] [2fC][mU][2fC][mU][2fU]-LIG-LINKER (SEQIDNO76) (SEQIDNO:169) OSC47A- [mA][2fA][2fG][mA][2fG][mC][2fU][mC] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 14 [2fA][mG][2fG][mU][2fC][mU][2fC][mU] 14 [2fG][mA][2fC][mC][2fU][mG][2fA] [2fG][mA][2fG][mG][2fG] [mG][2fC][mU][2fC][mU][2fU][dT]*[dT] (SEQIDNO77) (SEQIDNO:170) OSC47A- [mA][2fA][2fG][mA][2fG][mC][2fU][mC] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] [2fA][mG][2fG][mU][2fC][mU][2fC][mU] 15 [2fA][mG][2fC][mU][2fC][mU][2fU] 15 [2fG][mA][2fG][mG][2fG][dT]*[dT] [dT]*[dT](SEQIDNO:171) (SEQIDNO78) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 16 [2fA][mG][2fG][mU][2fC][mU][2fC][mU] 16 [2fA][mG][2fC][mU][2fC][mU][2fU] [2fG][mA][2fG][mG][2fG][dT]*[dT] [dT]*[dT](SEQIDNO:172) (SEQIDNO79) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 17 [2fA][mG][2fG][mU][2fC][mU][2fC][mU] 17 [2fA][mG][2fC][mU][2fC][mU][2fU] [2fG][mA][2fG][mG][2fG][dT]*[dT] (SEQIDNO:173) (SEQIDNO80) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 18 [mC][2fA][mG][2fG][mU][2fC][mU] 18 [2fA][mG][2fC][mU][2fC][mU][2fU] [2fC][2fU][2fG][2fA][2fG][2fG][2fG] (SEQIDNO:174) (SEQIDNO81) OSC48A AAGAGCUCAGGUCUCUGAGGG[dT][dT](SEQ OSC48S CCCUCAGAGACCUGAGCUCUU[dT][dT] IDNO82) (SEQIDNO:175) OSC49A AGAAGAGCUCAGGUCUCUGAG[dT][dT](SEQ OSC49S CUCAGAGACCUGAGCUCUUCU[dT][dT] IDNO:83) (SEQIDNO:176) OSC50A AUAGGGAGUGUCCAGGGACCC[dT][dT](SEQ OSC50S GGGUCCCUGGACACUCCCUAU[dT][dT] IDNO:84) (SEQIDNO:177) OSC51A UCCAUAGGGAGUGUCCAGGGA[dT][dT](SEQ OSC51S UCCCUGGACACUCCCUAUGGA[dT][dT] IDNO:85) (SEQIDNO:178) OSC52A AUCUCCAUAGGGAGUGUCCAG[dT][dT](SEQ OSC52S CUGGACACUCCCUAUGGAGAU[dT][dT] IDNO:86) (SEQIDNO:179) OSC53A UCAGUUCUGGCUGUGGCAGGU[dT][dT](SEQ OSC53S ACCUGCCACAGCCAGAACUGA[dT][dT] IDNO:87) (SEQIDNO:180) OSC54A UUCUACCCCCUGGGAGCUGCC[dT][dT](SEQ OSC54S GGCAGCUCCCAGGGGGUAGAA[dT][dT] IDNO:88) (SEQIDNO:181) OSC55A AAGCACAGGGCCGUUCUACCC[dT][dT](SEQ OSC55S GGGUAGAACGGCCCUGUGCUU[dT][dT] IDNO:89) (SEQIDNO:182) OSC56A UGUCUUAAGCACAGGGCCGUU[dT][dT](SEQ OSC56S AACGGCCCUGUGCUUAAGACA[dT][dT] IDNO:90) (SEQIDNO:183) OSC57A AGUGUCUUAAGCACAGGGCCG[dT][dT](SEQ OSC57S CGGCCCUGUGCUUAAGACACU[dT][dT] IDNO:91) (SEQIDNO:184) OSC58A UUUUUUGAGGAUGUGAAGCAA[dT][dT] OSC58S UUGCUUCACAUCCUCAAAAAA[dT][dT] (SEQIDNO:92) (SEQIDNO:185) OSC59A UUUUUUUGAGGAUGUGAAGCA[dT][dT] OSC59S UGCUUCACAUCCUCAAAAAAA[dT][dT] (SEQIDNO:93) (SEQIDNO:186)

TABLE-US-00018 TABLE6 LRP2 OSID AntisenseStrand(5TO3) OSID SenseStrand(5TO3) OSL1A UACUUUGUGAGCAAUCUUGAC[dT][dT](SEQ OSL1S GUCAAGAUUGCUCACAAAGUA[dT][dT] IDNO:187) (SEQIDNO:561) OSL2A AUUCACUUGGGAUACACUGAC[dT][dT](SEQ OSL2S GUCAGUGUAUCCCAAGUGAAU[dT][dT] IDNO:188) (SEQIDNO:562) OSL3A ACAUGAAAACUCAUUGUGCAA[dT][dT](SEQ OSL3S UUGCACAAUGAGUUUUCAUGU[dT][dT] IDNO:189) (SEQIDNO:563) OSL4A UCUUUACAGUCAUCUUCUCCA[dT][dT](SEQ OSL4S UGGAGAAGAUGACUGUAAAGAUA[dT][dT IDNO:190) (SEQIDNO:564) OSL5A UAUCUUUACAGUCAUCUUCUC[dT][dT](SEQ OSL5S GAGAAGAUGACUGUAAAGAUA[dT][dT] IDNO:191) (SEQIDNO:565) OSL6A AACAUUUAUGAACAUCAUGAG[dT][dT](SEQ OSL6S CUCAUGAUGUUCAUAAAUGUU[dT][dT] IDNO:192) (SEQIDNO:566) OSL7A UCACAAACUUUAUAAAUGGAG[dT][dT](SEQ OSL7S CUCCAUUUAUAAAGUUUGUGA[dT][dT] IDNO:193) (SEQIDNO:567) OSL8A AUCACAAACUUUAUAAAUGGA[dT][dT](SEQ OSL8S UCCAUUUAUAAAGUUUGUGAU[dT][dT] IDNO:194) (SEQIDNO:568) OSL9A AUACUACAGUAUUUUCCGGUA[dT][dT](SEQ OSL9S UACCGGAAAAUACUGUAGUAU[dT][dT] IDNO:195) (SEQIDNO:569) OSL10 UCAUACUACAGUAUUUUCCGG[dT][dT](SEQ OSL10S CCGGAAAAUACUGUAGUAUGA[dT][dT] A IDNO:196) (SEQIDNO:570) OSL11 ACAAAUUCCCCAUAUCUGGCA[dT][dT](SEQ OSL11S UGCCAGAUAUGGGGAAUUUGU[dT][dT] A IDNO:197) (SEQIDNO:571) OSL12 AAGAUAUACCCUUCUUCACAG[dT][dT](SEQ OSL12S CUGUGAAGAAGGGUAUAUCUU[dT][dT] A IDNO:198) (SEQIDNO:572) OSL13 UUAGCUUUGCAAUACUGUCCA[dT][dT](SEQ OSL13S UGGACAGUAUUGCAAAGCUAA[dT][dT] A IDNO:199) (SEQIDNO:573) OSL14 AUCAUUAGCUUUGCAAUACUG[dT][dT](SEQ OSL14S CAGUAUUGCAAAGCUAAUGAU[dT][dT] A IDNO:200) (SEQIDNO:574) OSL15 AAAGGAAUCAUUAGCUUUGCA[dT][dT](SEQ OSL15S UGCAAAGCUAAUGAUUCCUUU[dT][dT] A IDNO:201) (SEQIDNO:575) OSL16 AUGAAUAUCACCAAUUAACAA[dT][dT](SEQ OSL16S UUGUUAAUUGGUGAUAUUCAU[dT][dT] A IDNO:202) (SEQIDNO:576) OSL17 AAAAAACCUUAUUUUGCACGG[dT][dT](SEQ OSL17S CCGUGCAAAAUAAGGUUUUUU[dT][dT] A IDNO:203) (SEQIDNO:577) OSL18 UGAAAAAACCUUAUUUUGCAC[dT][dT](SEQ OSL18S GUGCAAAAUAAGGUUUUUUCA[dT][dT] A IDNO:204) (SEQIDNO:578) OSL19 AAUGUCAACUGAAAAAACCUU[dT][dT](SEQ OSL19S AAGGUUUUUUCAGUUGACAUU[dT][dT] A IDNO:205) (SEQIDNO:579) OSL20 UAAUGUCAACUGAAAAAACCU[dT][dT](SEQ OSL20S AGGUUUUUUCAGUUGACAUUA[dT][dT] A IDNO:206) (SEQIDNO:580) OSL21 UUAAACCAUUAAUGUCAACUG[dT][dT](SEQ OSL21S CAGUUGACAUUAAUGGUUUAA[dT][dT] A IDNO:207) (SEQIDNO:581) OSL22 UAUUUAAACCAUUAAUGUCAA[dT][dT](SEQ OSL22S UUGACAUUAAUGGUUUAAAUA[dT][dT] A IDNO:208) (SEQIDNO:582) OSL23 UAGAUUUUAUUAUUAACCCAG[dT][dT](SEQ OSL23S CUGGGUUAAUAAUAAAAUCUA[dT][dT] A IDNO:209) (SEQIDNO:583) OSL24 AUAGAUUUUAUUAUUAACCCA[dT][dT](SEQ OSL24S UGGGUUAAUAAUAAAAUCUAU[dT][dT] A IDNO:210) (SEQIDNO:584) OSL25 AAAUUUACCAUAUCUAUGCGG[dT][dT](SEQ OSL25S CCGCAUAGAUAUGGUAAAUUU[dT][dT] A IDNO:211) (SEQIDNO:585) OSL26 AAGUUUUCAGUUAUAAGGGUA[dT][dT](SEQ OSL26S UACCCUUAUAACUGAAAACUU[dT][dT] A IDNO:212) (SEQIDNO:586) OSL27 AAUAAAUAACCAACAGUUGGG[dT][dT](SEQ OSL27S CCCAACUGUUGGUUAUUUAUU[dT][dT] A IDNO:213) (SEQIDNO:587) OSL28 AGAAAAAUAAAUAACCAACAG[dT][dT](SEQ OSL28S CUGUUGGUUAUUUAUUUUUCU[dT][dT] A IDNO:214) (SEQIDNO:588) OSL29 AUAUCAUAUCCAGAGUUACCC[dT][dT](SEQ OSL29S GGGUAACUCUGGAUAUGAUAU[dT][dT] A IDNO:215) (SEQIDNO:589) OSL30 AGUUUCAAUGUAAUCAAACCG[dT][dT](SEQ OSL30S CGGUUUGAUUACAUUGAAACU[dT][dT] A IDNO:216) (SEQIDNO:590) OSL31 UUACAGUUUCAAUGUAAUCAA[dT][dT](SEQ OSL31S UUGAUUACAUUGAAACUGUAA[dT][dT] A IDNO:217) (SEQIDNO:591) OSL32 AUAAGUUACAGUUUCAAUGUA[dT][dT](SEQ OSL32S UACAUUGAAACUGUAACUUAU[dT][dT] A IDNO:218) (SEQIDNO:592) OSL33 UCUUUACACGGAUUGGUAGCA[dT][dT](SEQ OSL33S UGCUACCAAUCCGUGUAAAGA[dT][dT] A IDNO:219) (SEQIDNO:593) OSL34 AAAAUCAAUCCCGACAAAGAA[dT][dT](SEQ OSL34S UUCUUUGUCGGGAUUGAUUUU[dT][dT] A IDNO:220) (SEQIDNO:594) OSL35 UCUGAAAAAAAGAUAGUGCUG[dT][dT](SEQ OSL35S CAGCACUAUCUUUUUUUCAGA[dT][dT] A IDNO:221) (SEQIDNO:595) OSL36 AUCUGAAAAAAAGAUAGUGCU[dT][dT](SEQ OSL36S AGCACUAUCUUUUUUUCAGAU[dT][dT] A IDNO:222) (SEQIDNO:596) OSL37 AAAAAUCAUGUGUUUUGACAU[dT][dT](SEQ OSL37S AUGUCAAAACACAUGAUUUUU[dT][dT] A IDNO:223) (SEQIDNO:597) OSL38 UUUGCUUAAAAAUCAUGUGUU[dT][dT](SEQ OSL38S AACACAUGAUUUUUAAGCAAA[dT][dT] A IDNO:224) (SEQIDNO:598) OSL39 AACUUUCAACAUUUUCCACCC[dT][dT](SEQ OSL39S GGGUGGAAAAUGUUGAAAGUU[dT][dT] A IDNO:225) (SEQIDNO:599) OSL40 UUGAAAUCCAAUCAAAAGCCA[dT][dT](SEQ OSL40S UGGCUUUUGAUUGGAUUUCAA[dT][dT] A IDNO:226) (SEQIDNO:600) OSL41 UUUGAAAUCCAAUCAAAAGCC[dT][dT](SEQ OSL41S GGCUUUUGAUUGGAUUUCAAA[dT][dT] A IDNO:227) (SEQIDNO:601) OSL42 UAGAGAUUCUUUGAAAUCCAA[dT][dT](SEQ OSL42S UUGGAUUUCAAAGAAUCUCUA[dT][dT] A IDNO:228) (SEQIDNO:602) OSL43 AUAGAGAUUCUUUGAAAUCCA[dT][dT](SEQ OSL43S UGGAUUUCAAAGAAUCUCUAU[dT][dT] A IDNO:229) (SEQIDNO:603) OSL44 UUUAAAUACUGAACUACUGUG[dT][dT](SEQ OSL44S CACAGUAGUUCAGUAUUUAAA[dT][dT] A IDNO:230) (SEQIDNO:604) OSL45 UAUUUAAAUACUGAACUACUG[dT][dT](SEQ OSL45S CAGUAGUUCAGUAUUUAAAUA[dT][dT] A IDNO:231) (SEQIDNO:605) OSL46 AUAGAUACCCGGCAAAAGGAU[dT][dT](SEQ OSL46S AUCCUUUUGCCGGGUAUCUAU[dT][dT] A IDNO:232) (SEQIDNO:606) OSL47 AAGAGUAGUGUUUAUUACAGG[dT][dT](SEQ OSL47S CCCCUGUAAUAAACACUACUC[dT][dT] A IDNO:233) (SEQIDNO:607) OSL48 AUCAAAAUAGGCAUCUACCCA[dT][dT](SEQ OSL48S UGGGUAGAUGCCUAUUUUGAU[dT][dT] A IDNO:234) (SEQIDNO:608) OSL49 UCAAUUUUAUCAAAAUAGGCA[dT][dT](SEQ OSL49S UGCCUAUUUUGAUAAAAUUGA[dT][dT] A IDNO:235) (SEQIDNO:609) OSL50 UAAAUGCUCUCCAAAGAUGGC[dT][dT](SEQ OSL50S GCCAUCUUUGGAGAGCAUUUA[dT][dT] A IDNO:236) (SEQIDNO:610) OSL51 UCAAAUGCAGUAUGUAAGCAA[dT][dT](SEQ OSL51S UUGCUUACAUACUGCAUUUGA[dT][dT] A IDNO:237) (SEQIDNO:611) OSL52 UUCAAAUGCAGUAUGUAAGCA[dT][dT](SEQ OSL52S UGCUUACAUACUGCAUUUGAA[dT][dT] A IDNO:238) (SEQIDNO:612) OSL53 UGAUUACAGGCGUUAGAACCA[dT][dT](SEQ OSL53S UGGUUCUAACGCCUGUAAUCA[dT][dT] A IDNO:239) (SEQIDNO:613) OSL54 UGUUAUCAUGACAAUCAUCGA[dT][dT](SEQ OSL54S UCGAUGAUUGUCAUGAUAACA[dT][dT] A IDNO:240) (SEQIDNO:614) OSL55 UUAUCACAGGUGUAUUGGGUG[dT][dT](SEQ OSL55S CACCCAAUACACCUGUGAUAA[dT][dT] A IDNO:241) (SEQIDNO:615) OSL56 AUUAUCACAGGUGUAUUGGGU[dT][dT](SEQ OSL56S ACCCAAUACACCUGUGAUAAU[dT][dT] A IDNO:242) (SEQIDNO:616) OSL57 AGUUCUUUGAGAUACACUGGU[dT][dT](SEQ OSL57S ACCAGUGUAUCUCAAAGAACU[dT][dT] A IDNO:243) (SEQIDNO:617) OSL58 UCGAAUUGCAGUUCUUUUCAU[dT][dT](SEQ OSL58S AUGAAAAGAACUGCAAUUCGA[dT][dT] A IDNO:244) (SEQIDNO:618) OSL59 UCAAUACAUCGAUGAUUGGGG[dT][dT](SEQ OSL59S CCCCAAUCAUCGAUGUAUUGA[dT][dT] A IDNO:245) (SEQIDNO:619) OSL60 AACGAUAGGUCAAUACAUCGA[dT][dT](SEQ OSL60S UCGAUGUAUUGACCUAUCGUU[dT][dT] A IDNO:246) (SEQIDNO:620) OSL61 ACAAACGAUAGGUCAAUACAU[dT][dT](SEQ OSL61S AUGUAUUGACCUAUCGUUUGU[dT][dT] A IDNO:247) (SEQIDNO:621) OSL62 UCAAAAACACCAUCACAACGA[dT][dT](SEQID OSL62S UCGUUGUGAUGGUGUUUUUGA[dT][dT] A NO:248) (SEQIDNO:622) OSL63 UCACAUUCCCAGAAGUUCGGG[dT][dT](SEQ OSL63S CCCGAACUUCUGGGAAUGUGA[dT][dT] A IDNO:249) (SEQIDNO:623) OSL64 AUCACAUUCCCAGAAGUUCGG[dT][dT](SEQ OSL64S CCGAACUUCUGGGAAUGUGAU[dT][dT] A IDNO:250) (SEQIDNO:624) OSL65 UGAUGAAGGGCAAGUCUUGGG[dT][dT](SEQ OSL65S CCCAAGACUUGCCCUUCAUCA[dT][dT] A IDNO:251) (SEQIDNO:625) OSL66 AGAAUCAUUGGCAAGUAAGAA[dT][dT](SEQ OSL66S UUCUUACUUGCCAAUGAUUCU[dT][dT] A IDNO:252) (SEQIDNO:626) OSL67 UAUCACAUUCAUCUAUGUCUU[dT][dT](SEQ OSL67S AAGACAUAGAUGAAUGUGAUA[dT][dT] A IDNO:253) (SEQIDNO:627) OSL68 AAUAUCACAUUCAUCUAUGUC[dT][dT](SEQ OSL68S GACAUAGAUGAAUGUGAUAUU[dT][dT] A IDNO:254) (SEQIDNO:628) OSL69 AACAUGUAGCCUGUAUCACAC[dT][dT](SEQ OSL69S GUGUGAUACAGGCUACAUGUU[dT][dT] A IDNO:255) (SEQIDNO:629) OSL70 UCACUUUCUAACAUGUAGCCU[dT][dT](SEQ OSL70S AGGCUACAUGUUAGAAAGUGA[dT][dT] A IDNO:256) (SEQIDNO:630) OSL71 AUCACUUUCUAACAUGUAGCC[dT][dT](SEQ OSL71S GGCUACAUGUUAGAAAGUGAU[dT][dT] A IDNO:257) (SEQIDNO:631) OSL72 AAUGUAAGAACCAUUCUCGAC[dT][dT](SEQ OSL72S GUCGAGAAUGGUUCUUACAUU[dT][dT] A IDNO:258) (SEQIDNO:632) OSL73 UACAAUGUAAGAACCAUUCUC[dT][dT](SEQ OSL73S GAGAAUGGUUCUUACAUUGUA[dT][dT] A IDNO:259) (SEQIDNO:633) OSL74 AAAAUCAACAGCUACAAUGUA[dT][dT](SEQ OSL74S UACAUUGUAGCUGUUGAUUUU[dT][dT] A IDNO:260) (SEQIDNO:634) OSL75 AUUGAAUCAAAAUCAACAGCU[dT][dT](SEQ OSL75S AGCUGUUGAUUUUGAUUCAAU[dT][dT] A IDNO:261) (SEQIDNO:635) OSL76 UAAUUGAAUCAAAAUCAACAG[dT][dT](SEQ OSL76S CUGUUGAUUUUGAUUCAAUUA[dT][dT] A IDNO:262) (SEQIDNO:636) OSL77 AAGAUACGACCACUAAUUGAA[dT][dT](SEQ OSL77S UUCAAUUAGUGGUCGUAUCUU[dT][dT] A IDNO:263) (SEQIDNO:637) OSL78 AGUUUCAGUCAAGAUGAUGCU[dT][dT](SEQ OSL78S AGCAUCAUCUUGACUGAAACU[dT][dT] A IDNO:264) (SEQIDNO:638) OSL79 AAUAGUUUCAGUCAAGAUGAU[dT][dT](SEQ OSL79S AUCAUCUUGACUGAAACUAUU[dT][dT] A IDNO:265) (SEQIDNO:639) OSL80 UAUUGCAAUAGUUUCAGUCAA[dT][dT](SEQ OSL80S UUGACUGAAACUAUUGCAAUA[dT][dT] A IDNO:266) (SEQIDNO:640) OSL81 UCUAUUGCAAUAGUUUCAGUC[dT][dT](SEQ OSL81S GACUGAAACUAUUGCAAUAGA[dT][dT] A IDNO:267) (SEQIDNO:641) OSL82 AAUCUAUUGCAAUAGUUUCAG[dT][dT](SEQ OSL82S CUGAAACUAUUGCAAUAGAUU[dT][dT] A IDNO:268) (SEQIDNO:642) OSL83 AUUUUGGAGACUUCAAUUGUU[dT][dT](SEQ OSL83S AACAAUUGAAGUCUCCAAAAU[dT][dT] A IDNO:269) (SEQIDNO:643) OSL84 UUAGGUUUUUACUAAUCAGCA[dT][dT](SEQ OSL84S UGCUGAUUAGUAAAAACCUAA[dT][dT] A IDNO:270) (SEQIDNO:644) OSL85 UCAUUCUGGGAUCUAAUGCUA[dT][dT](SEQ OSL85S UAGCAUUAGAUCCCAGAAUGA[dT][dT] A IDNO:271) (SEQIDNO:645) OSL86 UUCAUUCUGGGAUCUAAUGCU[dT][dT](SEQ OSL86S AGCAUUAGAUCCCAGAAUGAA[dT][dT] A IDNO:272) (SEQIDNO:646) OSL87 AGUAGAUGCUCAUUCAUUCUG[dT][dT](SEQ OSL87S CAGAAUGAAUGAGCAUCUACU[dT][dT] A IDNO:273) (SEQIDNO:647) OSL88 AUUAUAAUCACAAAAGUCCAU[dT][dT](SEQ OSL88S AUGGACUUUUGUGAUUAUAAU[dT][dT] A IDNO:274) (SEQIDNO:648) OSL89 UCCAUUAUAAUCACAAAAGUC[dT][dT](SEQ OSL89S GACUUUUGUGAUUAUAAUGGA[dT][dT] A IDNO:275) (SEQIDNO:649) OSL90 UGCCGUAUAAUCAAAUCAC[dT][dT](SEQID OSL90S GUGUGAUUUGAUUAUACGGCA[dT][dT] A NO:276) (SEQIDNO:650) OSL91 AUAUUAUACAUUACAACUGAC[dT][dT](SEQ OSL91S GUCAGUUGUAAUGUAUAAUAU[dT][dT] A IDNO:277) (SEQIDNO:651) OSL92 AUUGAAUAUUAUACAUUACAA[dT][dT](SEQ OSL92S UUGUAAUGUAUAAUAUUCAAU[dT][dT] A IDNO:278) (SEQIDNO:652) OSL93 AAUUUGGUUGUUUCGAAGGAU[dT][dT](SEQ OSL93S AUCCUUCGAAACAACCAAAUU[dT][dT] A IDNO:279) (SEQIDNO:653) OSL94 ACGGAAUUUGGUUGUUUCGAA[dT][dT](SEQ OSL94S UUCGAAACAACCAAAUUCCGU[dT][dT] A IDNO:280) (SEQIDNO:654) OSL95 UUACAGUUAUUAAGAAAGGUU[dT][dT](SEQ OSL95S AACCUUUCUUAAUAACUGUAA[dT][dT] A IDNO:281) (SEQIDNO:655) OSL96 UCCAAAAAUUAUAUGUUGCCU[dT][dT](SEQ OSL96S AGGCAACAUAUAAUUUUUGGA[dT][dT] A IDNO:282) (SEQIDNO:656) OSL97 UUCCAAAAAUUAUAUGUUGCC[dT][dT](SEQ OSL97S GGCAACAUAUAAUUUUUGGAA[dT[dT] A IDNO:283) (SEQIDNO:657) OSL98 UCUAAACCAUUCUGUAUCCCU[dT][dT](SEQ OSL98S AGGGAUACAGAAUGGUUUAGA[dT][dT] A IDNO:284) (SEQIDNO:658) OSL99 AUCUAAACCAUUCUGUAUCCC[dT][dT](SEQ OSL99S GGGAUACAGAAUGGUUUAGAU[dT][dT] A IDNO:285) (SEQIDNO:659) OSL100 UUCAACAUCUAAACCAUUCUG[dT][dT](SEQ OSL100 CAGAAUGGUUUAGAUGUUGAA[dT[dT] A IDNO:286) S (SEQIDNO:660) OSL101 AUUUUCAACCCAAUAGAUGUA[dT][dT](SEQ OSL101 UACAUCUAUUGGGUUGAAAAU[dT][dT] A IDNO:287) S (SEQIDNO:661) OSL102 UAUAGAAGCAAAUACUGUCCU[dT][dT](SEQ OSL102 AGGACAGUAUUUGCUUCUAUA[dT][dT] A IDNO:288) S (SEQIDNO:662) OSL103 UAGAUAUAGAAGCAAAUACUG[dT][dT](SEQ OSL103 CAGUAUUUGCUUCUAUAUCUA[dT][dT] A IDNO:289) S (SEQIDNO:663) OSL104 UAAGGCCAGGUUCAUAGAAGG[dT][dT](SEQ OSL104 CCUUCUAUGAACCUGGCCU[dT][dT](SEQ A IDNO:290) S IDNO:664) OSL105 UCUUGAAAUCCAAUCUAAGGC[dT][dT](SEQ OSL105 GCCUUAGAUUGGAUUUCAAGA[dT][dT] A IDNO:291) S (SEQIDNO:665) OSL106 AUAAAGGUUUCUUGAAAUCCA[dT][dT](SEQ OSL106 UGGAUUUCAAGAAACCUUUAU[dT][dT] A IDNO:292) S (SEQIDNO:666) OSL107 UCAAAACCUCGAUUGACUGAG[dT][dT](SEQ OSL107 CUCAGUCAAUCGAGGUUUUGA[dT][dT] A IDNO:293) S (SEQIDNO:667) OSL108 UUCUGUAUCUGAUAUCUCCGU[dT][dT](SEQ OSL108 ACGGAGAUAUCAGAUACAGAA[dT][dT] A IDNO:294) S (SEQIDNO:668) OSL109 UUUCUGUAUCUGAUAUCUCCG[dT][dT](SEQ OSL109 CGGAGAUAUCAGAUACAGAAA[dT][dT] A IDNO:295) S (SEQIDNO:669) OSL110 UUUUUCUGUAUCUGAUAUCUC[dT][dT](SEQ OSL110 GAGAUAUCAGAUACAGAAAAA[dT][dT] A IDNO:296) S (SEQIDNO:670) OSL111 AUCAAUGUUUUUCUGUAUCUG[dT][dT](SEQ OSL111 CAGAUACAGAAAAACAUUGAU[dT][dT] A IDNO:297) S (SEQIDNO:671) OSL112 AUAAAGGAAAGAAUCAUGGAC[dT][dT](SEQ OSL112 GUCCAUGAUUCUUUCCUUUAU[dT][dT] A IDNO:298) S (SEQIDNO:672) OSL113 AAUAAAGGAAAGAAUCAUGGA[dT][dT](SEQ OSL113 UCCAUGAUUCUUUCCUUUAUU[dT][dT] A IDNO:299) S (SEQIDNO:673) OSL114 UCAGUAUAAUAAAGGAAAGAA[dT][dT](SEQ OSL114 UUCUUUCCUUUAUUAUACUGA[dT][dT] A IDNO:300) S (SEQIDNO:674) OSL115 UUUCAAUGACCUCAUACUGUU[dT][dT](SEQ OSL115 AACAGUAUGAGGUCAUUGAAA[dT][dT] A IDNO:301) S (SEQIDNO:675) OSL116 AUUUGGAACAUUAUCUCUCAA[dT][dT](SEQ OSL116 UUGAGAGAUAAUGUUCCAAAU[dT][dT] A IDNO:302) S (SEQIDNO:676) OSL117 AGAUUUGGAACAUUAUCUCUC[dT][dT](SEQ OSL117 GAGAGAUAAUGUUCCAAAUCU[dT][dT] A IDNO:303) S (SEQIDNO:677) OSL118 UCAGAUUUGGAACAUUAUCUC[dT][dT](SEQ OSL118 GAGAUAAUGUUCCAAAUCUGA[dT][dT] A IDNO:304) S (SEQIDNO:678) OSL119 UUGCUACAGCCAUUUGAGG[dT][dT](SEQID OSL119 CCUCAAAUGGCUGUAGCAA[dT][dT](SEQ A NO:305) S IDNO:679) OSL120 AUGAAAGAGUUAUAUGGAGAG[dT][dT](SEQ OSL120 CUCUCCAUAUAACUCUUUCAU[dT][dT] A IDNO:306) S (SEQIDNO:680) OSL121 ACAAUGAAAGAGUUAUAUGGA[dT][dT](SEQ OSL121 UCCAUAUAACUCUUUCAUUGU[dT][dT] A IDNO:307) S (SEQIDNO:681) OSL122 UGAAACAACAAUGAAAGAGUU[dT][dT](SEQ OSL122 AACUCUUUCAUUGUUGUUUCA[dT][dT] A IDNO:308) S (SEQIDNO:682) OSL123 AUUGAAACAACAAUGAAAGAG[dT][dT](SEQ OSL123 CUCUUUCAUUGUUGUUUCAAU[dT][dT] A IDNO:309) S (SEQIDNO:683) OSL124 AGCUAAAGCCUCUGAUUGCAG[dT][dT](SEQ OSL124 CUGCAAUCAGAGGCUUUAGCU[dT][dT] A IDNO:310) S (SEQIDNO:684) OSL125 AAGCUAAAGCCUCUGAUUGCA[dT][dT](SEQ OSL125 UGCAAUCAGAGGCUUUAGCUU[dT][dT] A IDNO:311) S (SEQIDNO:685) OSL126 ACAAUUCCAAGCUAAAGCCUC[dT][dT](SEQ OSL126 GAGGCUUUAGCUUGGAAUUGU[dT][dT] A IDNO:312) S (SEQIDNO:686) OSL127 UGACAAUUCCAAGCUAAAGCC[dT][dT](SEQ OSL127 GGCUUUAGCUUGGAAUUGUCA[dT][dT] A IDNO:313) S (SEQIDNO:687) OSL128 UGAAUGAUCUGACAAUUCCAA[dT][dT](SEQ OSL128 UUGGAAUUGUCAGAUCAUUCA[dT][dT] A IDNO:314) S (SEQIDNO:688) OSL129 AUGUUCAUCAGAGAAGAUCCA[dT][dT](SEQ OSL129 UGGAUCUUCUCUGAUGAACAU[dT][dT] A IDNO:315) S (SEQIDNO:689) OSL130 UAUUCCAUGUGUCACAAUGUU[dT][dT](SEQ OSL130 AACAUUGUGACACAUGGAAUA[dT][dT] A IDNO:316) S (SEQIDNO:690) OSL131 ACUUCUAUCAGUGUUUCAGAA[dT][dT](SEQ OSL131 UUCUGAAACACUGAUAGAAGU[dT][dT] A IDNO:317) S (SEQIDNO:691) OSL132 UAUUGAUCCGCAGAACUUCUA[dT][dT](SEQ OSL132 UAGAAGUUCUGCGGAUCAAUA[dT][dT] A IDNO:318) S (SEQIDNO:692) OSL133 UGUUCUUGGGAUCUACAACAA[dT][dT](SEQ OSL133 UUGUUGUAGAUCCCAAGAACA[dT][dT] A IDNO:319) S (SEQIDNO:693) OSL134 AAAGAACGCUCAAUCUUUGGU[dT][dT](SEQ OSL134 ACCAAAGAUUGAGCGUUCUUU[dT][dT] A IDNO:320) S (SEQIDNO:694) OSL135 UAAACGUAGCCAUCACUUCGG[dT][dT](SEQ OSL135 CCGAAGUGAUGGCUACGUUUA[dT][dT] A IDNO:321) S (SEQIDNO:695) OSL136 AUCUAAAGAAUCAUCAACCCA[dT][dT](SEQ OSL136 UGGGUUGAUGAUUCUUUAGAU[dT][dT] A IDNO:322) S (SEQIDNO:696) OSL137 UUAUAUCUAAAGAAUCAUCAA[dT][dT](SEQ OSL137 UUGAUGAUUCUUUAGAUAUAA[dT][dT] A IDNO:323) S (SEQIDNO:697) OSL138 AUAGAAUUUUCAAAAACAGUG[dT][dT](SEQ OSL138 CACUGUUUUUGAAAAUUCUAU[dT][dT] A IDNO:324) S (SEQIDNO:698) OSL139 UGAUAGAAUUUUCAAAAACAG[dT][dT](SEQ OSL139 CUGUUUUUGAAAAUUCUAUCA[dT][dT] A IDNO:325) S (SEQIDNO:699) OSL140 UUUCAAAUUCCUAUCUACCCA[dT][dT](SEQ OSL140 UGGGUAGAUAGGAAUUUGAAA[dT][dT] A IDNO:326) S (SEQIDNO:700) OSL141 UUUUCAAAUUCCUAUCUACCC[dT][dT](SEQ OSL141 GGGUAGAUAGGAAUUUGAAAA[dT][dT] A IDNO:327) S (SEQIDNO:701) OSL142 AUAUUGUCUCUUAUCACUGUG[dT][dT](SEQ OSL142 CACAGUGAUAAGAGACAAUAU[dT][dT] A IDNO:328) S (SEQIDNO:702) OSL143 UGAUAUUGUCUCUUAUCACUG[dT][dT](SEQ OSL143 CAGUGAUAAGAGACAAUAUCA[dT][dT] A IDNO:329) S (SEQIDNO:703) OSL144 UGAAAUGGCACAAUUCUUGCC[dT][dT](SEQ OSL144 GGCAAGAAUUGUGCCAUUUCA[dT][dT] A IDNO:330) S (SEQIDNO:704) OSL145 UGUUGAAAUGGCACAAUUCUU[dT][dT](SEQ OSL145 AAGAAUUGUGCCAUUUCAACA[dT][dT] A IDNO:331) S (SEQIDNO:705) OSL146 AAUUUUCUGUUGAAAUGGCAC[dT][dT](SEQ OSL146 GUGCCAUUUCAACAGAAAAUU[dT][dT] A IDNO:332) S (SEQIDNO:706) OSL147 AAAUUUUCUGUUGAAAUGGCA[dT][dT](SEQ OSL147 UGCCAUUUCAACAGAAAAUUU[dT][dT] A IDNO:333) S (SEQIDNO:707) OSL148 AUUAGACAAGGCAAAGAUGAG[dT][dT](SEQ OSL148 CUCAUCUUUGCCUUGUCUAAU[dT][dT] A IDNO:334) S (SEQIDNO:708) OSL149 ACAUUUAUUGUUUGGAAAGGU[dT][dT](SEQ OSL149 ACCUUUCCAAACAAUAAAUGU[dT][dT] A IDNO:335) S (SEQIDNO:709) OSL150 AUCACUUACACUGUCAUAGUC[dT][dT](SEQ OSL150 GACUAUGACAGUGUAAGUGAU[dT][dT] A IDNO:336) S (SEQIDNO:710) OSL151 UAGAUUCUAUCACUUACACUG[dT][dT](SEQ OSL151 CAGUGUAAGUGAUAGAAUCUA[dT][dT] A IDNO:337) S (SEQIDNO:711) OSL152 AGUAGAUUCUAUCACUUACAC[dT][dT](SEQ OSL152 GUGUAAGUGAUAGAAUCUACU[dT][dT] A IDNO:338) S (SEQIDNO:712) OSL153 UUUUGUGUGAAGUAGAUUCUA[dT][dT](SEQ OSL153 UAGAAUCUACUUCACACAAAA[dT][dT] A IDNO:339) S (SEQIDNO:713) OSL154 UAAAUUUUGUGUGAAGUAGAU[dT][dT](SEQ OSL154 AUCUACUUCACACAAAAUUUA[dT][dT] A IDNO:340) S (SEQIDNO:714) OSL155 UCUAGUAAUCCAGUCAAAGGC[dT][dT](SEQ OSL155 GCCUUUGACUGGAUUACUAGA[dT][dT] A IDNO:341) S (SEQIDNO:715) OSL156 AAUUCUUCUAGUAAUCCAGUC[dT][dT](SEQ OSL156 GACUGGAUUACUAGAAGAAUU[dT][dT] A IDNO:342) S (SEQIDNO:716) OSL157 UAAAUUCUUCUAGUAAUCCAG[dT][dT](SEQ OSL157 CUGGAUUACUAGAAGAAUUUA[dT][dT] A IDNO:343) S (SEQIDNO:717) OSL158 AUAAAUUCUUCUAGUAAUCCA[dT][dT](SEQ OSL158 UGGAUUACUAGAAGAAUUUAU[dT][dT] A IDNO:344) S (SEQIDNO:718) OSL159 AUAUACUGGCCAUAGAGAGUC[dT][dT](SEQ OSL159 GACUCUCUAUGGCCAGUAUAU[dT][dT] A IDNO:345) S (SEQIDNO:719) OSL160 UUCUUUGUGUGUACAAGUCAG[dT][dT](SEQ OSL160 CUGACUUGUACACACAAAGAA[dT][dT] A IDNO:346) S (SEQIDNO:720) OSL161 AAUUCUUUGUGUGUACAAGUC[dT][dT](SEQ OSL161 GACUUGUACACACAAAGAAUU[dT][dT] A IDNO:347) S (SEQIDNO:721) OSL162 UCGGUAAAUUCUUUGUGUGUA[dT][dT](SEQ OSL162 UACACACAAAGAAUUUACCGA[dT][dT] A IDNO:348) S (SEQIDNO:722) OSL163 UGUUACACUGUUGUUUCUGGU[dT][dT](SEQ OSL163 ACCAGAAACAACAGUGUAACA[dT][dT] A IDNO:349) S (SEQIDNO:723) OSL164 AUUGUUACACUGUUGUUUCUG[dT][dT](SEQ OSL164 CAGAAACAACAGUGUAACAAU[dT][dT] A IDNO:350) S (SEQIDNO:724) OSL165 AAACUGUUCACAAGGAUUGUU[dT][dT](SEQ OSL165 AACAAUCCUUGUGAACAGUUU[dT][dT] A IDNO:351) S (SEQIDNO:725) OSL166 ACAUCGUUCACCAUUGUCCAC[dT][dT](SEQ OSL166 GUGGACAAUGGUGAACGAUGU[dT][dT] A IDNO:352) S (SEQIDNO:726) OSL167 UGUUAUUGCACAUAAACUCCG[dT][dT](SEQ OSL167 CGGAGUUUAUGUGCAAUAACA[dT][dT] A IDNO:353) S (SEQIDNO:727) OSL168 UCUGUUAUUGCACAUAAACUC[dT][dT](SEQ OSL168 GAGUUUAUGUGCAAUAACAGA[dT][dT] A IDNO:354) S (SEQIDNO:728) OSL169 UUAUGACAUUUUGUGUAUCCA[dT][dT](SEQ OSL169 UGGAUACACAAAAUGUCAUAA[dT][dT] A IDNO:355) S (SEQIDNO:729) OSL170 UGAAUUAUGACAUUUUGUGUA[dT][dT](SEQ OSL170 UACACAAAAUGUCAUAAUUCA[dT][dT] A IDNO:356) S (SEQIDNO:730) OSL171 UUUGAAUUAUGACAUUUUGUG[dT][dT](SEQ OSL171 CACAAAAUGUCAUAAUUCAAA[dT][dT] A IDNO:357) S (SEQIDNO:731) OSL172 UACAAAUAUUUGAAUUAUGAC[dT][dT](SEQ OSL172 GUCAUAAUUCAAAUAUUUGUA[dT][dT] A IDNO:358) S (SEQIDNO:732) OSL173 AAAUAAACGCGAGGAAUACAA[dT][dT](SEQ OSL173 UUGUAUUCCUCGCGUUUAUUU[dT][dT] A IDNO:359) S (SEQIDNO:733) OSL174 AAUAAGUAGGGUUUUCAUCAC[dT][dT](SEQ OSL174 GUGAUGAAAACCCUACUUAUU[dT][dT] A IDNO:360) S (SEQIDNO:734) OSL175 UCACAAUACCAAUGUUGAGGA[dT][dT](SEQ OSL175 UCCUCAACAUUGGUAUUGUGA[dT][dT] A IDNO:361) S (SEQIDNO:735) OSL176 UGUUUCUUGAUCACAAUACCA[dT][dT](SEQ OSL176 UGGUAUUGUGAUCAAGAAACA[dT][dT] A IDNO:362) S (SEQIDNO:736) OSL177 AACAAUCUGUUUCUUGAUCAC[dT][dT](SEQ OSL177 GUGAUCAAGAAACAGAUUGUU[dT][dT] A IDNO:363) S (SEQIDNO:737) OSL178 UUUACACAGAGAAACUCGGAA[dT][dT](SEQ OSL178 UUCCGAGUUUCUCUGUGUAAA[dT][dT] A IDNO:364) S (SEQIDNO:738) OSL179 AUUUACACAGAGAAACUCGGA[dT][dT](SEQ OSL179 UCCGAGUUUCUCUGUGUAAAU[dT][dT] A IDNO:365) S (SEQIDNO:739) OSL180 UUCUGAUUCUCAUCGUAGCCG[dT][dT](SEQ OSL180 CGGCUACGAUGAGAAUCAGAA[dT][dT] A IDNO:366) S (SEQIDNO:740) OSL181 AUUUUCAGAGCAAGUUCUCCU[dT][dT](SEQ OSL181 AGGAGAACUUGCUCUGAAAAU[dT][dT] A IDNO:367) S (SEQIDNO:741) OSL182 AUAUCUUUGGGAUACACAGUC[dT][dT](SEQ OSL182 GACUGUGUAUCCCAAAGAUAU[dT][dT] A IDNO:368) S (SEQIDNO:742) OSL183 AGGUAAACUGAUUCUGUUGGC[dT][dT](SEQ OSL183 GCCAACAGAAUCAGUUUACCU[dT][dT] A IDNO:369) S (SEQIDNO:743) OSL184 AUAGAAACUGGUUAAGGUGUC[dT][dT](SEQ OSL184 GACACCUUAACCAGUUUCUAU[dT][dT] A IDNO:370) S (SEQIDNO:744) OSL185 ACAAUAGAAACUGGUUAAGGU[dT][dT](SEQ OSL185 ACCUUAACCAGUUUCUAUUGU[dT][dT] A IDNO:371) S (SEQIDNO:745) OSL186 UCAUCAAUAUCAACACAAGUC[dT][dT](SEQ OSL186 GACUUGUGUUGAUAUUGAUGA[dT][dT] A IDNO:372) S (SEQIDNO:746) OSL187 AGAUGUAGGAGCCUAUUACAU[dT][dT](SEQ OSL187 AUGUAAUAGGCUCCUACAUCU[dT][dT] A IDNO:373) S (SEQIDNO:747) OSL188 UCGAUGUUACUGUUUUGCCGG[dT][dT](SEQ OSL188 CCGGCAAAACAGUAACAUCGA[dT][dT] A IDNO:374) S (SEQIDNO:748) OSL189 UUGCUAAAAAUGAGAUAGGGU[dT][dT](SEQ OSL189 ACCCUAUCUCAUUUUUAGCAA[dT][dT] A IDNO:375) S (SEQIDNO:749) OSL190 AUUUCUCAAAUAGUAACGGUU[dT][dT](SEQ OSL190 AACCGUUACUAUUUGAGAAAU[dT][dT] A IDNO:376) S (SEQIDNO:750) OSL191 AAUUUCUCAAAUAGUAACGGU[dT][dT](SEQ OSL191 ACCGUUACUAUUUGAGAAAUU[dT][dT] A IDNO:377) S (SEQIDNO:751) OSL192 AAAUUUCUCAAAUAGUAACGG[dT][dT](SEQ OSL192 CCGUUACUAUUUGAGAAAUUU[dT][dT] A IDNO:378) S (SEQIDNO:752) OSL193 AGUUAAAUUUCUCAAAUAGUA[dT][dT](SEQ OSL193 UACUAUUUGAGAAAUUUAACU[dT][dT] A IDNO:379) S (SEQIDNO:753) OSL194 AUCUAUAGUUAAAUUUCUCAA[dT][dT](SEQ OSL194 UUGAGAAAUUUAACUAUAGAU[dT][dT] A IDNO:380) S (SEQIDNO:754) OSL195 UAAAAAUAGCCAUCUAUAGUU[dT][dT](SEQ OSL195 AACUAUAGAUGGCUAUUUUUA[dT][dT] A IDNO:381) S (SEQIDNO:755) OSL196 AUCUAAUGCCACAACAUUGUC[dT][dT](SEQ OSL196 GACAAUGUUGUGGCAUUAGAU[dT][dT] A IDNO:382) S (SEQIDNO:756) OSL197 AAUCCAAUACAAUCUCUUCUC[dT][dT](SEQ OSL197 GAGAAGAGAUUGUAUUGGAUU[dT][dT] A IDNO:383) S (SEQIDNO:757) OSL198 ACAUUCUCUCAAUGACUUGCC[dT][dT](SEQ OSL198 GGCAAGUCAUUGAGAGAAUGU[dT][dT] A IDNO:384) S (SEQIDNO:758) OSL199 AUGAUUGUCUCCUUGUUUGUC[dT][dT](SEQ OSL199 GACAAACAAGGAGACAAUCAU[dT][dT] A IDNO:385) S (SEQIDNO:759) OSL200 AUUAUCACAGACUUGUUGGUU[dT][dT](SEQ OSL200 AACCAACAAGUCUGUGAUAAU[dT][dT] A IDNO:386) S (SEQIDNO:760) OSL201 UUCAAAAAUGGUAAUAGCGAA[dT][dT](SEQ OSL201 UUCGCUAUUACCAUUUUUGAA[dT][dT] A IDNO:387) S (SEQIDNO:761) OSL202 UCUUCAAAAAUGGUAAUAGCG[dT][dT](SEQ OSL202 CGCUAUUACCAUUUUUGAAGA[dT][dT] A IDNO:388) S (SEQIDNO:762) OSL203 AUUUGUUUCCCUUUUCCACUG[dT][dT](SEQ OSL203 CAGUGGAAAAGGGAAACAAAU[dT][dT] A IDNO:389) S (SEQIDNO:763) OSL204 AUUUGAUCCAUCAUAUUUGUU[dT][dT](SEQ OSL204 AACAAAUAUGAUGGAUCAAAU[dT][dT] A IDNO:390) S (SEQIDNO:764) OSL205 UAUAUGGAUGGUACACAUGGA[dT][dT](SEQ OSL205 UCCAUGUGUACCAUCCAUAUA[dT][dT] A IDNO:391) S (SEQIDNO:765) OSL206 AAAGAAGACGGUCUUCAUCAG[dT][dT](SEQ OSL206 CUGAUGAAGACCGUCUUCUUU[dT][dT] A IDNO:392) S (SEQIDNO:766) OSL207 UGAAUUCUGUGAAGUUGUCAC[dT][dT](SEQ OSL207 GUGACAACUUCACAGAAUUCA[dT][dT] A IDNO:393) S (SEQIDNO:767) OSL208 ACAAUGUCCACUUGUACACUG[dT][dT](SEQ OSL208 CGGUGUACAAGUGGACAUUGU[dT][dT] A IDNO:394) S (SEQIDNO:768) OSL209 ACACAAUGUCCACUUGUACAC[dT][dT](SEQ OSL209 GUGUACAAGUGGACAUUGUGU[dT][dT] A IDNO:395) S (SEQIDNO:769) OSL210 UUUUUGCAUUCGAACAUAGUA[dT][dT](SEQ OSL210 UACUAUGUUCGAAUGCAAAAA[dT][dT] A IDNO:396) S (SEQIDNO:770) OSL211 AUGGUUUUUGCAUUCGAACAU[dT][dT](SEQ OSL211 AUGUUCGAAUGCAAAAACCAU[dT][dT] A IDNO:397) S (SEQIDNO:771) OSL212 AUACAAACAUGGUUUUUGCAU[dT][dT](SEQ OSL212 AUGCAAAAACCAUGUUUGUAU[dT][dT] A IDNO:398) S (SEQIDNO:772) OSL213 AUCACAUUUCCAAUAUGGCGG[dT][dT](SEQ OSL213 CCGCCAUAUUGGAAAUGUGAU[dT][dT] A IDNO:399) S (SEQIDNO:773) OSL214 UGAAGUUCUUCAUCUGAACCA[dT][dT](SEQ OSL214 UGGUUCAGAUGAAGAACUUCA[dT][dT] A IDNO:400) S (SEQIDNO:774) OSL215 AUAAAUGCAGCGAUUGUUGUC[dT][dT](SEQ OSL215 GACAACAAUCGCUGCAUUUAU[dT][dT] A IDNO:401) S (SEQIDNO:775) OSL216 AUUCUGUACAAGGUUUAGGGG[dT][dT](SEQ OSL216 CCCCUAAACCUUGUACAGAAU[dT][dT] A IDNO:402) S (SEQIDNO:776) OSL217 UAUUCUGUACAAGGUUUAGGG[dT][dT](SEQ OSL217 CCCUAAACCUUGUACAGAAUA[dT][dT] A IDNO:403) S (SEQIDNO:777) OSL218 AUUCAUAUUCUGUACAAGGUU[dT][dT](SEQ OSL218 AACCUUGUACAGAAUAUGAAU[dT][dT] A IDNO:404) S (SEQIDNO:778) OSL219 UAUUCAUAUUCUGUACAAGGU[dT][dT](SEQ OSL219 ACCUUGUACAGAAUAUGAAUA[dT][dT] A IDNO:405) S (SEQIDNO:779) OSL220 UUAUAUUCAUAUUCUGUACAA[dT][dT](SEQ OSL220 UUGUACAGAAUAUGAAUAUAA[dT][dT] A IDNO:406) S (SEQIDNO:780) OSL221 UAUUGCAACCCAGUUCAUCGG[dT][dT](SEQ OSL221 CCGAUGAACUGGGUUGCAAUA[dT][dT] A IDNO:407) S (SEQIDNO:781) OSL222 AUAUUUUCAGCACAUGUUCUU[dT][dT](SEQ OSL222 AAGAACAUGUGCUGAAAAUAU[dT][dT] A IDNO:408) S (SEQIDNO:782) OSL223 UUAAUUGGGUACAAUUUUGCU[dT][dT](SEQ OSL223 AGCAAAAUUGUACCCAAUUAA[dT][dT] A IDNO:409) S (SEQIDNO:783) OSL224 AAAAACAUUGGUUUCGAACCC[dT][dT](SEQ OSL224 GGGUUCGAAACCAAUGUUUUU[dT][dT] A IDNO:410) S (SEQIDNO:784) OSL225 UGUCAAAAACAUUGGUUUCGA[dT][dT](SEQ OSL225 UCGAAACCAAUGUUUUUGACA[dT][dT] A IDNO:411) S (SEQIDNO:785) OSL226 UUCGAAUUCGGACAUUGUCAG[dT][dT](SEQ OSL226 CUGACAAUGUCCGAAUUCGAA[dT][dT] A IDNO:412) S (SEQIDNO:786) OSL227 AUUAUAUUUUCGAAUUCGGAC[dT][dT](SEQ OSL227 GUCCGAAUUCGAAAAUAUAAU[dT][dT] A IDNO:413) S (SEQIDNO:787) OSL228 AGAUUAUAUUUUCGAAUUCGG[dT][dT](SEQ OSL228 CCGAAUUCGAAAAUAUAAUCU[dT][dT] A IDNO:414) S (SEQIDNO:788) OSL229 UCAUCUUGAAGAUACUCUGAG[dT][dT](SEQ OSL229 CUCAGAGUAUCUUCAAGAUGA[dT][dT] A IDNO:415) S (SEQIDNO:789) OSL230 UAUAUUCCUCAUCUUGAAGAU[dT][dT](SEQ OSL230 AUCUUCAAGAUGAGGAAUAUA[dT][dT] A IDNO:416) S (SEQIDNO:790) OSL231 UUUGAUAGCACCAAACCUAGAGCCC[dT][dT] OSL231 GGGCUCUAGGUUUGGUGCUAUCAAA[dT] A-1 (SEQIDNO:417) S-1 [dT](SEQIDNO:791) OSL231 UUUGAUAGCACCAAACCUAGAGCCC[dT]*[dT] OSL231 GGGCUCUAGGUUUGGUGCUAUCAAA[dT]* A-2 (SEQIDNO:418) S-2 [dT](SEQIDNO:792) OSL231 [mU][mU][mU][mG][mA][mU][mA][mG][mC][ OSL231 [mG][mG][mG][mC][mU][mC][mU][mA][m A-3 mA][mC][mC][mA][mA][mA][mC][mC][mU][ S-3 G][mG][mU][mU][mU][mG][mG][mU][mG] mA][mG][mA][mG][mC][mC][mC][dT]*[dT] [mC][mU][mA][mU][mC][mA][mA][mA][dT] (SEQIDNO:419) *[dT](SEQIDNO:793) OSL231 [mU][mU][mU][mG][mA][mU][mA][mG][mC][ OSL231 [mG][mG][mG][mC][mU][mC][mU][mA][m A-4 mA][mC][mC][mA][mA][mA][mC][mC][mU][ S-4 G][mG][mU][mU][mU][mG][mG][mU][mG] mA][mG][mA][mG][mC][mC][mC][dT]*[dT] [mC][mU][mA][mU][mC][mA][mA][mA] (SEQIDNO:420) (SEQIDNO:794) OSL231 [mU][mU][mU][mG][mA][mU][mA][mG][mC][ OSL231 [mG][mG][mG][mC][mU][mC][mU][mA][m A-5 mA][mC][mC][mA][mA][mA][mC][mC][mU][ S-5 G][mG][mU][mU][mU][mG][mG][mU][mG] mA][mG][mA][mG][mC][mC][mC](SEQID [mC][mU][mA][mU][mC][mA][mA][mA][dT] NO:421) *[dT](SEQIDNO:795) OSL231 [mU][mU][mU][mG][mA][mU][mA][mG][mC][ OSL231 [mG][mG][mG][mC][mU][mC][mU][mA][m A-6 mA][mC][mC][mA][mA][mA][mC][mC][mU][ S-6 G][mG][mU][mU][mU][mG][mG][mU][mG] mA][mG][mA][mG][mC][mC][mC](SEQID [mC][mU][mA][mU][mC][mA][mA][mA] NO:422) (SEQIDNO:796) OSL231 [mU][mU][mU][mG][mA][mU][mA][mG][mC][ OSL231 GGGCUCUAGGUUUGGUGCUAUCAAA[dT]* A-7 mA][mC][mC][mA][mA][mA][mC][mC][mU][ S-7 [dT](SEQIDNO:797) mA][mG][mA][mG][mC][mC][mC][dT]*[dT] (SEQIDNO:423) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fG][mG][2fG][mC][2fU][mC][2fU][mA] A-8 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-8 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mC][2fU][mA][2fG][mA][2fG][mC][2fC] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] [mC][dT]*[dT](SEQIDNO:424) [2fA][dT]*[dT](SEQIDNO:798) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fG][mG][2fG][mC][2fU][mC][2fU][mA] A-9 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-9 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mC][2fU][mA][2fG][mA][2fG][mC][2fC] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] [mC](SEQIDNO:425) [2fA][dT]*[dT](SEQIDNO:799) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fG][mG][2fG][mC][2fU][mC][2fU][mA] A-10 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-10 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mC][2fU][mA][2fG][mA][2fG][mC][2fC] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] [mC][dT]*[dT](SEQIDNO:426) [2fA](SEQIDNO:800) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fG][mG][2fG][mC][2fU][mC][2fU][mA] A-11 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-11 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mC][2fU][mA][2fG][mA][2fC][mC][2fC] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] [mC](SEQIDNO:427) [2fA](SEQIDNO:801) OSL231 [2fU][mU][2fU][mG][2fA][mU][2fA][mG] OSL231 [mG][2fG][mG][2fC][mU][2fC][mU][2fA] A-12 [2fC][mA][2fC][mC][2fA][mA][2fA][mC] S-12 [mG][2fG][mU][2fU][mU][2fG][mG][2Fu] [2fC][mU][2fA][mG][2fA][mG][2fC][mC] [mG][2fC][mU][2fA][mU][2fC][mA][2fA] [2fC][dT]*[dT](SEQIDNO:428) [mA][dT]*[dT](SEQIDNO:802) OSL231 [mU][2fA][mU][2fC][mA][2fA][mA][2fC] OSL231 [2fG][mG][2fG][mC][2fU][mC][2fU][mA] A-13 [mC][2fU][mC][2fG][mA][2fU][mA][2fG] S-13 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mC][2fA][mA][2fC][mA][2fC][mC][2fG] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] [mC](SEQIDNO:429) [2fA]-LINKER-LIG(SEQIDNO:803) OSL231 [mU][2fU][2fU][2fG][2fA][2fU][2fA][2fG] OSL231 [2fU][mC][2fU][mA][2fG][mG][2fU][mU] A-14 [2fC][2fA][2fC][2fC][2fA][2fA][2fA] S-14 [2fU][mG][2fG][mU][2fG][mC][2fU][mA] [2fC][2fC][2fU][2fA][2fG][2fA][2fG] [2fU][mC][2fA][mA][2fA][dT]*[dT] [2fC][2fC][2fC][dT]*[dT](SEQID (SEQIDNO:804) NO:430) OSL231 [mU][2fU][2fU][2fG][2fA][2fU][2fA][2fG] OSL231 [2fU][mU][2fU][mG][2fG][mU][2fG][mC] A-15 [2fC][2fA][2fC][2fC][2fA][2fA][2fA] S-15 [2fU][mA][2fU][mC][2fA][mA][2fA][dT] [2fC][2fC][2fU][2fA][2fG][2fA][2fG] *[dT](SEQIDNO:805) [2fC][2fC][2fC][dT]*[dT](SEQID NO:431) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fU][mU][2fU][mG][2fG][mU][2fG][mC] A-16 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-16 [2fU][mA][2fU][mC][2fA][mA][2fA][dT] [mC][2fU][mA][2fG][mA][2fG][mC][2fC] *[dT](SEQIDNO:806) [mC][dT]*[dT](SEQIDNO:432) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fU][mU][2fU][mG][2fG][mU][2fG][mC] A-17 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-17 [2fU][mA][2fU][mC][2fA][mA][2fA] [mC][2fU][mA][2fG][mA][2fG][mC](SEQ (SEQIDNO:807) IDNO:433) OSL231 [mU][2fU][mU][2fG][mA][2fU][mA][2fG] OSL231 [2fU][mU][2fU][mG][2fG][mU][2fG][mC] A-18 [mC][2fA][mC][2fC][mA][2fA][mA][2fC] S-18 [2fU][mA][2fU][mC][2fA][mA][2fA] [2fC][2fU][2fA][2fG][2fA][2fG][2fC] (SEQIDNO:808) (SEQIDNO:434) OSL232 UCAAAGUUGGGGAUGUAGGCA[dT][dT](SEQ OSL232 UGCCUACAUCCCCAACUUUGA[dT][dT] A IDNO:435) S (SEQIDNO:809) OSL233 UCAGUUUCAGGUCAACUUCCU[dT][dT](SEQ OSL233 AGGAAGUUGACCUGAAACUGA[dT][dT] A IDNO:436) S (SEQIDNO:810) OSL234 UACGUAUUUCAGUUUCAGGUC[dT][dT](SEQ OSL234 GACCUGAAACUGAAAUACGUA[dT][dT] A IDNO:437) S (SEQIDNO:811) OSL235 UUACGUAUUUCAGUUUCAGGU[dT][dT](SEQ OSL235 ACCUGAAACUGAAAUACGUAA[dT][dT] A IDNO:438) S (SEQIDNO:812) OSL236 AGUUUAGCCACCUCAAUGCGU[dT][dT](SEQ OSL236 ACGCAUUGAGGUGGCUAAACU[dT][dT] A IDNO:439) S (SEQIDNO:813) OSL237 AACAUAAGCCCUAGUUUGGGA[dT][dT](SEQ OSL237 UCCCAAACUAGGGCUUAUGUU[dT][dT] A IDNO:440) S (SEQIDNO:814) OSL238 UCGAUUUUAGGUUCCUUUCCC[dT][dT](SEQ OSL238 GGGAAAGGAACCUAAAAUCGA[dT][dT] A IDNO:441) S (SEQIDNO:815) OSL239 UCGAAAACCAGGAUGUUGCGG[dT][dT](SEQ OSL239 CCGCAACAUCCUGGUUUUCGA[dT][dT] A IDNO:442) S (SEQIDNO:816) OSL240 UCAAAUAAUCGAUAGAAAGGC[dT][dT](SEQ OSL240 GCCUUUCUAUCGAUUAUUUGA[dT][dT] A IDNO:443) S (SEQIDNO:817) OSL241 UUGUUCAAAUAAUCGAUAGAA[dT][dT](SEQ OSL241 UUCUAUCGAUUAUUUGAACAA[dT][dT] A IDNO:444) S (SEQIDNO:818) OSL242 UUAUGGUUUCAAUAACGUCCU[dT][dT](SEQ OSL242 AGGACGUUAUUGAAACCAUAA[dT][dT] A IDNO:445) S (SEQIDNO:819) OSL243 UUUUAUGGUUUCAAUAACGUC[dT][dT](SEQ OSL243 GACGUUAUUGAAACCAUAAAA[dT][dT] A IDNO:446) S (SEQIDNO:820) OSL244 AUUUUAUGGUUUCAAUAACGU[dT][dT](SEQ OSL244 ACGUUAUUGAAACCAUAAAAU[dT][dT] A IDNO:447) S (SEQIDNO:821) OSL245 UUUGCAAUGACUCUCCUAUCAGUCC[dT][dT] OSL245 GGACUGAUAGGAGAGUCAUUGCAAA[dT][dT] A-1 (SEQIDNO:448) S-1 (SEQIDNO:822) OSL245 UUUGCAAUGACUCUCCUAUCAGUCC[dT]*[dT] OSL245 GGACUGAUAGGAGAGUCAUUGCAA]A[dT] A-2 (SEQIDNO:449) S-2 *[dT](SEQIDNO:823) OSL245 [mU][mU][mU][mG][mC][mA][mA][mU][mG][ OSL245 [mG][mG][mA][mC][mU][mG][mA][mU][m A-3 mA][mC][mU][mC][mU][mC][mC][mU][mA][ S-3 A][mG][mG][mA][mG][mA][mG][mU][mC][ mU][mC][mA][mG][mU][mC][mC][dT]*[dT] mA][mU][mU][mG][mC][mA][mA][mA][dT (SEQIDNO:450) ]*[dT](SEQIDNO:824) OSL245 [mU][mU][mU][mG][mC][mA][mA][mU][mG][ OSL245 [mG][mG][mA][mC][mU][mG][mA][mU][m A-4 mA][mC][mU][mC][mU][mC][mC][mU][mA][ S-4 A][mG][mG][mA][mG][mA][mG][mU][mC][ mU][mC][mA][mG][mU][mC][mC][dT]*[dT] mA][mU][mU][mG][mC][mA][mA][mA](SE (SEQIDNO:451) QIDNO:825) OSL245 [mU][mU][mU][mG][mC][mA][mA][mU][mG][ OSL245 [mG][mG][mA][mC][mU][mG][mA][mU][m A-5 mA][mC][mU][mC][mU][mC][mC][mU][mA][ S-5 A][mG][mG][mA][mG][mA][mG][mU][mC][ mU][mC][mA][mG][mU][mC][mC](SEQID mA][mU][mU][mG][mC][mA][mA][mA][dT] NO:452) *[dT](SEQIDNO:826) OSL245 [mU][mU][mU][mG][mC][mA][mA][mU][mG][ OSL245 [mG][mG][mA][mC][mU][mG][mA][mU][m A-6 mA][mC][mU][mC][mU][mC][mC][mU][mA][ S-6 A][mG][mG][mA][mG][mA][mG][mU][mC][ mU][mC][mA][mG][mU][mC][mC](SEQID mA][mU][mU][mG][mC][mA][mA][mA] NO:453) (SEQIDNO:827) OSL245 [mU][mU][mU][mG][mC][mA][mA][mU][mG][ OSL245 GGACUGAUAGGAGAGUCAUUGCAAA[dT]* A-7 mA][mC][mU][mC][mU][mC][mC][mU][mA][ S-7 [dT](SEQIDNO:828) mU][mC][mA][mG][mU][mC][mC][dT]*[dT] (SEQIDNO:454) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 [2fG][mG][2fA][mC][2fU][mG][2fA][mU] A-8 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-8 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fA][mU][2fC][mA][2fG][mU][2fC] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] [mC][dT]*[dT](SEQIDNO:455) [2fA][dT]*[dT](SEQIDNO:829) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 [2fG][mG][2fA][mC][2fU][mG][2fA][mU] A-9 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-9 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fA][mU][2fC][mA][2fG][mU][2fC] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] [mC](SEQIDNO:456) [2fA][dT]*[dT](SEQIDNO:830) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 [2fG][mG][2fA][mC][2fU][mG][2fA][mU] A-10 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-10 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fA][mU][2fC][mA][2fG][mU][2fC] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] [mC][dT]*[dT](SEQIDNO:457) [2fA](SEQIDNO:831) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 [2fG][mG][2fA][mC][2fU][mG][2fA][mU] A-11 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-11 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fA][mU][2fC][mA][2fC][mU][2fC] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] [mC](SEQIDNO:458) [2fA](SEQIDNO:832) OSL245 [2fU][mU][2fU][mG][2fC][mA][2fA][mU] OSL245 [mG][2fG][mA][2fC][mU][2fG][mA][2fU] A-12 [2fG][mA][2fC][mU][2fC][mU][2fC][mC] S-12 [mA][2fG][mG][2fA][mG][2fA][mG][2fU] [2fU][mA][2fU][mC][2fA][mG][2fU][mC] [mC][2fA][mU][2fU][mG][2fC][mA][2fA] [2fC][dT]*[dT](SEQIDNO:459) [mA][dT]*[dT](SEQIDNO:833) OSL245 [mU][2fA][mU][2fC][mC][2fU][mA][2fA] OSL245 [2fG][mG][2fA][mC][2fU][mG][2fA][mU] A-13 [mG][2fU][mC][2fA][mC][2fA][mC][2fG] S-13 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fU][mU][2fG][mA][2fC][mU][2fG] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] [mC](SEQIDNO:460) [2fA](SEQIDNO:834) OSL245 [mU][2fU][2fU][2fG][2fC][2fA][2fA][2fU] OSL245 [2fU][mG][2fA][mU][2fA][mG][2fG][mA] A-14 [2fG][2fA][2fC][2fU][2fC][2fU][2fC] S-14 [2fG][mA][2fG][mU][2fC][mA][2fU][mU] [2fC][2fU][2fA][2fU][2fC][2fA][2fG] [2fG][mC][2fA][mA][2fA][dT]*[dT] [2fU][2fC][2fC][dT]*[dT](SEQIDNO: (SEQIDNO:835) 461) OSL245 [mU][2fU][2fU][2fG][2fC][2fA][2fA][2fU] OSL245 [2fG][mA][2fG][mA][2fG][mU][2fC][mA] A-15 [2fG][2fA][2fC][2fU][2fC][2fU][2fC] S-15 [2fU][mU][2fG][mC][2fA][mA][2fA][dT] [2fC][2fU][2fA][2fU][2fC][2fA][2fG] *[dT](SEQIDNO:836) [2fU][2fC][2fC][dT]*[dT](SEQID NO:462) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 [2fG][mA][2fG][mA][2fG][mU][2fC][mA] A-16 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-16 [2fU][mU][2fG][mC][2fA][mA][2fA][dT] [mU][2fA][mU][2fC][mA][2fG][mU][2fC] *[dT](SEQIDNO:837) [mC][dT]*[dT](SEQIDNO:463) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 [2fG][mA][2fG][mA][2fG][mU][2fC][mA] A-17 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-17 [2fU][mU][2fG][mC][2fA][mA][2fA] [mU][2fA][mU][2fC][mA][2fG][mU](SEQ (SEQIDNO:838) IDNO:464) OSL245 [mU][2fU][mU][2fG][mC][2fA][mA][2fU] OSL245 ACCAGUUAUACUGGAUAUCUA[dT][dT] A-18 [mG][2fA][mC][2fU][mC][2fU][mC][2fC] S-18 (SEQIDNO:840) [2fU][2fA][2fU][2fC][2fA][2fG][2fU] (SEQIDNO:465) OSL246 UAGAUAUCCAGUAUAACUGGU[dT][dT](SEQ OSL246 GGGAGAAGUAUGGAAACAAAA[dT][dT] A IDNO:466) S (SEQIDNO:841) OSL247 UUUUGUUUCCAUACUUCUCCC[dT][dT](SEQ OSL247 AAGUAUGGAAACAAAAUAAAU[dT][dT] A IDNO:467) S (SEQIDNO:842) OSL248 AUUUAUUUUGUUUCCAUACUU[dT][dT](SEQ OSL248 UUCAUCAACUCAGAUACAAUA[dT][dT] A IDNO:468) S (SEQIDNO:843) OSL249 UAUUGUAUCUGAGUUGAUGAA[dT][dT](SEQ OSL249 CGGAGGAAAUUGCUAUUUUGA[dT][dT] A IDNO:469) S (SEQIDNO:844) OSL250 UCAAAAUAGCAAUUUCCUCCG[dT][dT](SEQ OSL250 AGGAAAUUGCUAUUUUGAUGA[dT][dT] A IDNO:470) S (SEQIDNO:845) OSL251 UCAUCAAAAUAGCAAUUUCCU[dT][dT](SEQ OSL251 CACCGGAAAAUAUUGUGAAAU[dT][dT] A IDNO:471) S (SEQIDNO:846) OSL252 AUUUCACAAUAUUUUCCGGUG[dT][dT](SEQ OSL252 UUGUGAAAUGGCGUUUUCAAA[dT][dT] A IDNO:472) S (SEQIDNO:847) OSL253 UUUGAAAACGCCAUUUCACAA[dT][dT](SEQ OSL253 CAGGAUUCUUCCACUAUAGAA[dT][dT] A IDNO:473) S (SEQIDNO:848) OSL254 UUCUAUAGUGGAAGAAUCCUG[dT][dT](SEQ OSL254 GGCAGAUCUUAACAUGGAUAU[dT][dT] A IDNO:474) S (SEQIDNO:849) OSL255 AUAUCCAUGUUAAGAUCUGCC[dT][dT](SEQ OSL255 GGCAAUGAGUGAAGACUUUGU[dT][dT] A IDNO:475) S (SEQIDNO:850) OSL256 ACAAAGUCUUCACUCAUUGCC[dT][dT](SEQ OSL256 AUCUGAAAAUGUGGAUAAUAA[dT][dT] A IDNO:476) S (SEQIDNO:851) OSL257 UUAUUAUCCACAUUUUCAGAU[dT][dT](SEQ OSL257 ACCAGUUAUACUGGAUAUCUA[dT][dT] A IDNO:477) S (SEQIDNO:840) OSL258 UCUUAUUAUCCACAUUUUCAG[dT][dT](SEQ OSL258 CUGAAAAUGUGGAUAAUAAGA[dT][dT] A IDNO:478) S (SEQIDNO:852) OSL259 UCCAUAAUUCUUAUUAUCCAC[dT][dT](SEQ OSL259 GUGGAUAAUAAGAAUUAUGGA[dT][dT] A IDNO:479) S (SEQIDNO:853) OSL260 UUCCAUAAUUCUUAUUAUCCA[dT][dT](SEQ OSL260 UGGAUAAUAAGAAUUAUGGAA[dT][dT] A IDNO:480) S (SEQIDNO:854) OSL261 UUUUCGUUUGAAGAGAUUCCA[dT][dT](SEQ OSL261 UGGAAUCUCUUCAAACGAAAA[dT][dT] A IDNO:481) S (SEQIDNO:855) OSL262 UAGAUUUUCGUUUGAAGAGAU[dT][dT](SEQ OSL262 AUCUCUUCAAACGAAAAUCUA[dT][dT] A IDNO:482) S (SEQIDNO:856) OSL263 UUUAGAUUUUCGUUUGAAGAG[dT][dT](SEQ OSL263 CUCUUCAAACGAAAAUCUAAA[dT][dT] A IDNO:483) S (SEQIDNO:857) OSL264 UUGUUUAGAUUUUCGUUUGAA[dT][dT](SEQ OSL264 UUCAAACGAAAAUCUAAACAA[dT][dT] A IDNO:484) S (SEQIDNO:858) OSL265 UAGUUUGUUUAGAUUUUCGUU[dT][dT] OSL265 AACGAAAAUCUAAACAAACUA[dT][dT] A (SEQIDNO:485) S (SEQIDNO:859) OSL266 UUUCAAAGUUGGUAGUUUGUU[dT][dT](SEQ OSL266 AACAAACUACCAACUUUGAAA[dT][dT] A IDNO:486) S (SEQIDNO:860) OSL267 AUUGGAUUUUCAAAGUUGGUA[dT][dT](SEQ OSL267 UACCAACUUUGAAAAUCCAAU[dT][dT] A IDNO:487) S (SEQIDNO:861) OSL268 AUAGAUUGGAUUUUCAAAGUU[dT][dT](SEQ OSL268 AACUUUGAAAAUCCAAUCUAU[dT][dT] A IDNO:488) S (SEQIDNO:862) OSL269 UUAAAAGUGUCUUCUGUUGCA[dT][dT](SEQ OSL269 UGCAACAGAAGACACUUUUAA[dT][dT] A IDNO:489) S (SEQIDNO:863) OSL270 UCUUUAACAAGAUUUGCGGUG[dT][dT](SEQ OSL270 CACCGCAAAUCUUGUUAAAGA[dT][dT] A IDNO:490) S (SEQIDNO:864) OSL271 UCUUCUUUAACAAGAUUUGCG[dT][dT](SEQ OSL271 CGCAAAUCUUGUUAAAGAAGA[dT][dT] A IDNO:491) S (SEQIDNO:865) OSL272 UGGUAUAGCUAUACUUCAGAG[dT][dT](SEQ OSL272 CUCUGAAGUAUAGCUAUACCA[dT][dT] A IDNO:492) S (SEQIDNO:866) OSL273 AUUAUUCCCUAAAUAGCUGGU[dT][dT](SEQ OSL273 ACCAGCUAUUUAGGGAAUAAU[dT][dT] A IDNO:493) S (SEQIDNO:867) OSL274 UAAUUAUUCCCUAAAUAGCUG[dT][dT](SEQ OSL274 CAGCUAUUUAGGGAAUAAUUA[dT][dT] A IDNO:494) S (SEQIDNO:868) OSL275 AUAUAUGUGCAAAAGUGUGUU[dT][dT](SEQ OSL275 AACACACUUUUGCACAUAUAU[dT][dT] A IDNO:495) S (SEQIDNO:869) OSL276 AAAUAUAUGUGCAAAAGUGUG[dT][dT](SEQ OSL276 CACACUUUUGCACAUAUAUUU[dT][dT] A IDNO:496) S (SEQIDNO:870) OSL277 AACUUUUUUCAUCUGUUUGUA[dT][dT](SEQ OSL277 UACAAACAGAUGAAAAAAGUU[dT][dT] A IDNO:497) S (SEQIDNO:871) OSL278 UAAAGUACUGAAUGUUAACUU[dT][dT](SEQ OSL278 AAGUUAACAUUCAGUACUUUA[dT][dT] A IDNO:498) S (SEQIDNO:872) OSL279 UUUUUUUCAUAAAGUACUGAA[dT][dT](SEQ OSL279 UUCAGUACUUUAUGAAAAAAA[dT][dT] A IDNO:499) S (SEQIDNO:873) OSL280 UAUUUUUUUCAUAAAGUACUG[dT][dT](SEQ OSL280 CAGUACUUUAUGAAAAAAAUA[dT][dT] A IDNO:500) S (SEQIDNO:874) OSL281 AUUUGUAAAAAUAUGAGACGG[dT][dT](SEQ OSL281 CCGUCUCAUAUUUUUACAAAU[dT][dT] A IDNO:501) S (SEQIDNO:875) OSL282 ACAUUGUGAUAAUUAUUUGUA[dT][dT](SEQ OSL282 UACAAAUAAUUAUCACAAUGU[dT][dT] A IDNO:502) S (SEQIDNO:876) OSL283 AUACAUAUAGUACAUUGUGAU[dT][dT](SEQ OSL283 AUCACAAUGUACUAUAUGUAU[dT][dT] A IDNO:503) S (SEQIDNO:877) OSL284 AUAUACAUAUAGUACAUUGUG[dT][dT](SEQ OSL284 CACAAUGUACUAUAUGUAUAU[dT][dT] A IDNO:504) S (SEQIDNO:878) OSL285 AAAGAUAUACAUAUAGUACAU[dT][dT](SEQ OSL285 AUGUACUAUAUGUAUAUCUUU[dT][dT] A IDNO:505) S (SEQIDNO:879) OSL286 AUUACCUUCAGACAACUUCAG[dT][dT](SEQ OSL286 CUGAAGUUGUCUGAAGGUAAU[dT][dT] A IDNO:506) S (SEQIDNO:880) OSL287 UAUUUAUAGUAUUACCUUCAG[dT][dT](SEQ OSL287 CUGAAGGUAAUACUAUAAAUA[dT][dT] A IDNO:507) S (SEQIDNO:881) OSL288 UAAUCUUUCCAAAAUUUACAA[dT][dT](SEQ OSL288 UUGUAAAUUUUGGAAAGAUUA[dT][dT] A IDNO:508) S (SEQIDNO:882) OSL289 AGUAACAGGAUAAUCUUUCCA[dT][dT](SEQ OSL289 UGGAAAGAUUAUCCUGUUACU[dT][dT] A IDNO:509) S (SEQIDNO:883) OSL290 AUUCAGUAACAGGAUAAUCUU[dT][dT](SEQ OSL290 AAGAUUAUCCUGUUACUGAAU[dT][dT] A IDNO:510) S (SEQIDNO:884) OSL291 UAGCAAAUUCAGUAACAGGAU[dT][dT](SEQ OSL291 AUCCUGUUACUGAAUUUGCUA[dT][dT] A IDNO:511) S (SEQIDNO:885) OSL292 UUAGCAAAUUCAGUAACAGGA[dT][dT](SEQ OSL292 UCCUGUUACUGAAUUUGCUAA[dT][dT] A IDNO:512) S (SEQIDNO:886) OSL293 UCUUUAUUAGCAAAUUCAGUA[dT][dT](SEQ OSL293 UACUGAAUUUGCUAAUAAAGA[dT][dT] A IDNO:513) S (SEQIDNO:887) OSL294 AUCAUUUACUAUAAUGAUCAC[dT][dT](SEQ OSL294 GUGAUCAUUAUAGUAAAUGAU[dT][dT] A IDNO:514) S (SEQIDNO:888) OSL295 UUCUUGUUGGAUCAUUUACUA[dT][dT](SEQ OSL295 UAGUAAAUGAUCCAACAAGAA[dT][dT] A IDNO:515) S (SEQIDNO:889) OSL296 UCAAUUCCUUUUCUUGUUGGA[dT][dT](SEQ OSL296 UCCAACAAGAAAAGGAAUUGA[dT][dT] A IDNO:516) S (SEQIDNO:890) OSL297 AUUUUAUAGGAAAUAUGAGUG[dT][dT](SEQ OSL297 CACUCAUAUUUCCUAUAAAAU[dT][dT] A IDNO:517) S (SEQIDNO:891) OSL298 UAAUUUUAUAGGAAAUAUGAG[dT][dT](SEQ OSL298 CUCAUAUUUCCUAUAAAAUUA[dT][dT] A IDNO:518) S (SEQIDNO:892) OSL299 UGCUAAUGUGUAAAAAUGGAC[dT][dT](SEQ OSL299 GUCCAUUUUUACACAUUAGCA[dT][dT] A IDNO:519) S (SEQIDNO:893) OSL300 UUGAACAUUAAUUAAGUGCUA[dT][dT](SEQ OSL300 UAGCACUUAAUUAAUGUUCAA[dT][dT] A IDNO:520) S (SEQIDNO:894) OSL301 AUUGAACAUUAAUUAAGUGCU[dT][dT](SEQ OSL301 AGCACUUAAUUAAUGUUCAAU[dT][dT] A IDNO:521) S (SEQIDNO:895) OSL302 AUAUUGAACAUUAAUUAAGUG[dT][dT](SEQ OSL302 CACUUAAUUAAUGUUCAAUAU[dT][dT] A IDNO:522) S (SEQIDNO:896) OSL303 AAAUUGACAUGUAAUAUUGAA[dT][dT](SEQ OSL303 UUCAAUAUUACAUGUCAAUUU[dT][dT] A IDNO:523) S (SEQIDNO:897) OSL304 AUCAACAUAGCCAUUAAUCAA[dT][dT](SEQ OSL304 UUGAUUAAUGGCUAUGUUGAU[dT][dT] A IDNO:524) S (SEQIDNO:898) OSL305 UCUAUACAACACAUAGUGGCC[dT][dT](SEQ OSL305 GGCCACUAUGUGUUGUAUAGA[dT][dT] A IDNO:525) S (SEQIDNO:899) OSL306 AUGUCUAUACAACACAUAGUG[dT][dT](SEQ OSL306 CACUAUGUGUUGUAUAGACAU[dT][dT] A IDNO:526) S (SEQIDNO:900) OSL307 ACUGAAUUGCUUUUCCUACCU[dT][dT](SEQ OSL307 AGGUAGGAAAAGCAAUUCAGU[dT][dT] A IDNO:527) S (SEQIDNO:901) OSL308 AAAUAAAAAUGUUGUCUUGGC[dT][dT](SEQ OSL308 GCCAAGACAACAUUUUUAUUU[dT][dT] A IDNO:528) S (SEQIDNO:902) OSL309 AUCACAAAUAAAAAUGUUGUC[dT][dT](SEQ OSL309 GACAACAUUUUUAUUUGUGAU[dT][dT] A IDNO:529) S (SEQIDNO:903) OSL310 AAUGAUAUGGGAUUUCCUCAU[dT][dT](SEQ OSL310 AUGAGGAAAUCCCAUAUCAUU[dT][dT] A IDNO:530) S (SEQIDNO:904) OSL311 AUUAACCACAAACUCAAUGCA[dT][dT](SEQ OSL311 UGCAUUGAGUUUGUGGUUAAU[dT][dT] A IDNO:531) S (SEQIDNO:905) OSL312 UUUAAUUAACCACAAACUCAA[dT][dT](SEQ OSL312 UUGAGUUUGUGGUUAAUUAAA[dT][dT] A IDNO:532) S (SEQIDNO:906) OSL313 UUUGGUUUCAGAAAUUCAGCU[dT][dT](SEQ OSL313 AGCUGAAUUUCUGAAACCAAA[dT][dT] A IDNO:533) S (SEQIDNO:907) OSL314 UUAUGAAGACACAGAUUUGGU[dT][dT](SEQ OSL314 ACCAAAUCUGUGUCUUCAUAA[dT][dT] A IDNO:534) S (SEQIDNO:908) OSL315 UUUCAUAGAAACAAAAACCCA[dT][dT](SEQ OSL315 UGGGUUUUUGUUUCUAUGAAA[dT][dT] A IDNO:535) S (SEQIDNO:909) OSL316 AUGAUAUUUUCAUAGAAACAA[dT][dT](SEQ OSL316 UUGUUUCUAUGAAAAUAUCAU[dT][dT] A IDNO:536) S (SEQIDNO:910) OSL317 UAUAAUGAUAUUUUCAUAGAA[dT][dT](SEQ OSL317 UUCUAUGAAAAUAUCAUUAUA[dT][dT] A IDNO:537) S (SEQIDNO:911) OSL318 UGAUUAUAAUGAUAUUUUCAU[dT][dT](SEQ OSL318 AUGAAAAUAUCAUUAUAAUCA[dT][dT] A IDNO:538) S (SEQIDNO:912) OSL319 AUAAAUAGUGAUUAUAAUGAU[dT][dT](SEQ OSL319 AUCAUUAUAAUCACUAUUUAU[dT][dT] A IDNO:539) S (SEQIDNO:913) OSL320 AAAAGCUUAAUAAGAAUGGUU[dT][dT](SEQ OSL320 AACCAUUCUUAUUAAGCUUUU[dT][dT] A IDNO:540) S (SEQIDNO:914) OSL321 AAAAAGCUUAAUAAGAAUGGU[dT][dT](SEQ OSL321 ACCAUUCUUAUUAAGCUUUUU[dT][dT] A IDNO:541) S (SEQIDNO:915) OSL322 UAAAUGUACACAUUUAGCCAC[dT][dT](SEQ OSL322 GUGGCUAAAUGUGUACAUUUA[dT][dT] A IDNO:542) S (SEQIDNO:916) OSL323 AUAAAUGUACACAUUUAGCCA[dT][dT](SEQ OSL323 UGGCUAAAUGUGUACAUUUAU[dT][dT] A IDNO:543) S (SEQIDNO:917) OSL324 UAUAAAUGUACACAUUUAGCC[dT][dT](SEQ OSL324 GGCUAAAUGUGUACAUUUAUA[dT][dT] A IDNO:544) S (SEQIDNO:918) OSL325 UUCUAAUAUAAAUGUACACAU[dT][dT](SEQ OSL325 AUGUGUACAUUUAUAUUAGAA[dT][dT] A IDNO:545) S (SEQIDNO:919) OSL326 AAGAAUUAAAGAAAAGAUCUG[dT][dT](SEQ OSL326 CAGAUCUUUUCUUUAAUUCUU[dT][dT] A IDNO:546) S (SEQIDNO:920) OSL327 AAUAAGAAUUAAAGAAAAGAU[dT][dT](SEQ OSL327 AUCUUUUCUUUAAUUCUUAUU[dT][dT] A IDNO:547) S (SEQIDNO:921) OSL328 AAACCAAUAAGAAUUAAAGAA[dT][dT](SEQ OSL328 UUCUUUAAUUCUUAUUGGUUU[dT][dT] A IDNO:548) S (SEQIDNO:922) OSL329 ACUAUACCCACUAUUUAAGAG[dT][dT](SEQ OSL329 CUCUUAAAUAGUGGGUAUAGU[dT][dT] A IDNO:549) S (SEQIDNO:923) OSL330 ACAAAUGUGCAAUAUUAGCAC[dT][dT](SEQ OSL330 GUGCUAAUAUUGCACAUUUGU[dT][dT] A IDNO:550) S (SEQIDNO:924) OSL331 AACAAAUGUGCAAUAUUAGCA[dT][dT](SEQ OSL331 UGCUAAUAUUGCACAUUUGUU[dT][dT] A IDNO:551) S (SEQIDNO:925) OSL332 AUGUUUCAUUCAUUCAUCCAU[dT][dT](SEQ OSL332 AUGGAUGAAUGAAUGAAACAU[dT][dT] A IDNO:552) S (SEQIDNO:926) OSL333 AGUAGUAUAUGUUUCAUUCAU[dT][dT](SEQ OSL333 AUGAAUGAAACAUAUACUACU[dT][dT] A IDNO:553) S (SEQIDNO:927) OSL334 AAUCAGUAGUAUAUGUUUCAU[dT][dT](SEQ OSL334 AUGAAACAUAUACUACUGAUU[dT][dT] A IDNO:554) S (SEQIDNO:928) OSL335 AAAUAAUCAGUAGUAUAUGUU[dT][dT](SEQ OSL335 AACAUAUACUACUGAUUAUUU[dT][dT] A IDNO:555) S (SEQIDNO:929) OSL336 AAUCAAAGUAAUUACAGUCAG[dT][dT](SEQ OSL336 CUGACUGUAAUUACUUUGAUU[dT][dT] A IDNO:556) S (SEQIDNO:930) OSL337 AUCUAAUCAAAGUAAUUACAG[dT][dT](SEQ OSL337 CUGUAAUUACUUUGAUUAGAU[dT][dT] A IDNO:557) S (SEQIDNO:931) OSL338 UUAUUUCCAGUUGUUUAUCUA[dT][dT](SEQ OSL338 UAGAUAAACAACUGGAAAUAA[dT][dT] A IDNO:558) S (SEQIDNO:932) OSL339 UUAUUAGAACUUUUUCAGCAG[dT][dT](SEQ OSL339 CUGCUGAAAAAGUUCUAAUAA[dT][dT] A IDNO:559) S (SEQIDNO:933) OSL340 UUUAUUAGAACUUUUUCAGCA[dT][dT](SEQ OSL340 UGCUGAAAAAGUUCUAAUAAA[dT][dT] A IDNO:560) S (SEQIDNO:934)

TABLE-US-00019 TABLE5A CD320ANTISENSETARGET SEQ target start ID ID position position targetsequence Location Size NO: OSC1 2-24 2 TGCGCGTGCGCAGGGATAAGAGA 5UTR 21 996 OSC2 4-26 4 CGCGTGCGCAGGGATAAGAGAGC 5UTR 21 997 OSC3 48-70 48 GCGCCGCTGTGGGGACAGCATGA 5UTR 21 998 OSC4 63-85 63 CAGCATGAGCGGCGGTTGGATGG 5UTR- 21 999 CDS OSC5 164-186 164 CCGCCGCGAGCCCGCTTTCCACC CDS 21 1000 OSC6 222-244 222 CTCGTGCCCACCCACCAAGTTCC CDS 21 1001 OSC7 225-247 225 GTGCCCACCCACCAAGTTCCAGT CDS 21 1002 OSC8 227-249 227 GCCCACCCACCAAGTTCCAGTGC CDS 21 1003 OSC9 244-266 244 CAGTGCCGCACCAGTGGCTTATG CDS 21 1004 OSC10 249-271 249 CCGCACCAGTGGCTTATGCGTGC CDS 21 1005 OSC11 282-304 282 GCGCTGCGACAGGGACTTGGACT CDS 21 1006 OSC12 306-328 306 CAGCGATGGCAGCGATGAGGAGG CDS 21 1007 OSC13 390-412 390 CCCCTGCACCGGCGTCAGTGACT CDS 21 1008 OSC14 411-433 411 CTGCTCTGGGGGAACTGACAAGA CDS 21 1009 OSC15 414-436 414 CTCTGGGGGAACTGACAAGAAAC CDS 21 1010 OSC16 417-439 417 TGGGGGAACTGACAAGAAACTGC CDS 21 1011 OSC17 422-466 422 GAACTGACAAGAAACTGCGCAACTG CDS 25 1012 OSC18 483-505 483 CACGCTGAGCGATGACTGCATTC CDS 21 1013 OSC19 484-506 484 ACGCTGAGCGATGACTGCATTCC CDS 21 1014 OSC20 487-509 487 CTGAGCGATGACTGCATTCCACT CDS 21 1015 OSC21 489-511 489 GAGCGATGACTGCATTCCACTCA CDS 21 1016 OSC22 520-542 520 TGCGACGGCCACCCAGACTGTCC CDS 21 1017 OSC23 556-578 556 GAGCTCGGCTGTGGAACCAATGA CDS 21 1018 OSC24 560-582 560 TCGGCTGTGGAACCAATGAGATC CDS 21 1019 OSC25 561-583 561 CGGCTGTGGAACCAATGAGATCC CDS 21 1020 OSC26 564-586 564 CTGTGGAACCAATGAGATCCTCC CDS 21 1021 OSC27 626-648 626 TGGAGAGTGTCACCTCTCTCAGG CDS 21 1022 OSC28 641-663 641 CTCTCAGGAATGCCACAACCATG CDS 21 1023 OSC29 689-711 689 TCCCCTCTGTCGGGAATGCCACA CDS 21 1024 OSC30 695-717 695 CTGTCGGGAATGCCACATCCTCC CDS 21 1025 OSC31 719-741 719 CTGCCGGAGACCAGTCTGGAAGC CDS 21 1026 OSC32 741-763 741 CCCAACTGCCTATGGGGTTATTG CDS 21 1027 OSC33 767-789 767 CTGCTGCGGTGCTCAGTGCAAGC CDS 21 1028 OSC34 795-817 795 CACCGCCACCCTCCTCCTTTTGT CDS 21 1029 OSC35 797-819 797 CCGCCACCCTCCTCCTTTTGTCC CDS 21 1030 OSC36 843-865 843 CCGCCCACTGGGGTTACTGGTGG CDS 21 1031 OSC37 852-874 852 GGGGTTACTGGTGGCCATGAAGG CDS 21 1032 OSC38 857-879 857 TACTGGTGGCCATGAAGGAGTCC CDS 21 1033 OSC39 874-896 874 GAGTCCCTGCTGCTGTCAGAACA CDS 21 1034 OSC40 878-900 878 CCCTGCTGCTGTCAGAACAGAAG CDS 21 1035 OSC41 881-903 881 TGCTGCTGTCAGAACAGAAGACC CDS 21 1036 OSC42 884-906 884 TGCTGTCAGAACAGAAGACCTCG CDS 21 1037 OSC43 901-923 901 ACCTCGCTGCCCTGAGGACAAGC CDS 21 1038 OSC44 907-929 907 CTGCCCTGAGGACAAGCACTTGC CDS- 21 1039 3UTR OSC45 971-993 971 GAGCAGTGATGCGGATGGGTACC 3UTR 21 1040 OSC46 995-1017 995 GGGCACACCAGCCCTCAGAGACC 3UTR 21 1041 OSC47 1006-1026 1006 CCCTCAGAGACCTGAGCTCTT 3UTR 21 1393 OSC48 1006-1028 1006 CCCTCAGAGACCTGAGCTCTTCT 3UTR 21 1042 OSC49 1008-1030 1008 CTCAGAGACCTGAGCTCTTCTGG 3UTR 21 1043 OSC50 1082-1104 1082 GGGTCCCTGGACACTCCCTATGG 3UTR 21 1044 OSC51 1085-1107 1085 TCCCTGGACACTCCCTATGGAGA 3UTR 21 1045 OSC52 1088-1110 1088 CTGGACACTCCCTATGGAGATCC 3UTR 21 1046 OSC53 1129-1151 1129 ACCTGCCACAGCCAGAACTGAGG 3UTR 21 1047 OSC54 1163-1185 1163 GGCAGCTCCCAGGGGGTAGAACG 3UTR 21 1048 OSC55 1176-1198 1176 GGGTAGAACGGCCCTGTGCTTAA 3UTR 21 1049 OSC56 1182-1204 1182 AACGGCCCTGTGCTTAAGACACT 3UTR 21 1050 OSC57 1184-1206 1184 CGGCCCTGTGCTTAAGACACTCC 3UTR 21 1051 OSC58 1237-1259 1237 TTGCTTCACATCCTCAAAAAAAA 3UTR 21 1052 OSC59 1238-1260 1238 TGCTTCACATCCTCAAAAAAAAA 3UTR 21 1053

TABLE-US-00020 TABLE6A LRP2ANTISENSETARGET SEQ Target Start ID ID position position Targetsequence Location Size NO: OSL1 512-534 512 GTCAAGATTGCTCACAAAGTACA CDS 21 1054 OSL2 566-588 566 GTCAGTGTATCCCAAGTGAATAC CDS 21 1055 OSL3 763-785 763 TTGCACAATGAGTTTTCATGTGG CDS 21 1056 OSL4 939-961 939 TGGAGAAGATGACTGTAAAGATA CDS 21 1057 OSL5 941-963 941 GAGAAGATGACTGTAAAGATAAT CDS 21 1058 OSL6 992-1014 992 CTCATGATGTTCATAAATGTTCC CDS 21 1059 OSL7 1053- 1053 CTCCATTTATAAAGTTTGTGATG CDS 21 1060 1075 OSL8 1054- 1054 TCCATTTATAAAGTTTGTGATGG CDS 21 1061 1076 OSL9 1119- 1119 TACCGGAAAATACTGTAGTATGA CDS 21 1062 1141 OSL10 1121- 1121 CCGGAAAATACTGTAGTATGACT CDS 21 1063 1143 OSL11 1267- 1267 TGCCAGATATGGGGAATTTGTGA CDS 21 1064 1289 OSL12 1329- 1329 CTGTGAAGAAGGGTATATCTTGG CDS 21 1065 1351 OSL13 1356- 1356 TGGACAGTATTGCAAAGCTAATG CDS 21 1066 1378 OSL14 1360- 1360 CAGTATTGCAAAGCTAATGATTC CDS 21 1067 1382 OSL15 1366- 1366 TGCAAAGCTAATGATTCCTTTGG CDS 21 1068 1388 OSL16 1423- 1423 TTGTTAATTGGTGATATTCATGG CDS 21 1069 1445 OSL17 1541- 1541 CCGTGCAAAATAAGGTTTTTTCA CDS 21 1070 1563 OSL18 1543- 1543 GTGCAAAATAAGGTTTTTTCAGT CDS 21 1071 1565 OSL19 1552- 1552 AAGGTTTTTTCAGTTGACATTAA CDS 21 1072 1574 OSL20 1553- 1553 AGGTTTTTTCAGTTGACATTAAT CDS 21 1073 1575 OSL21 1562- 1562 CAGTTGACATTAATGGTTTAAAT CDS 21 1074 1584 OSL22 1565- 1565 TTGACATTAATGGTTTAAATATC CDS 21 1075 1587 OSL23 1638- 1638 CTGGGTTAATAATAAAATCTATC CDS 21 1076 1660 OSL24 1639- 1639 TGGGTTAATAATAAAATCTATCT CDS 21 1077 1661 OSL25 1680- 1680 CCGCATAGATATGGTAAATTTGG CDS 21 1078 1702 OSL26 1719- 1719 TACCCTTATAACTGAAAACTTGG CDS 21 1079 1741 OSL27 1767- 1767 CCCAACTGTTGGTTATTTATTTT CDS 21 1080 1789 OSL28 1772- 1772 CTGTTGGTTATTTATTTTTCTCA CDS 21 1081 1794 OSL29 1895- 1895 GGGTAACTCTGGATATGATATCG CDS 21 1082 1917 OSL30 1942- 1942 CGGTTTGATTACATTGAAACTGT CDS 21 1083 1964 OSL31 1946- 1946 TTGATTACATTGAAACTGTAACT CDS 21 1084 1968 OSL32 1951- 1951 TACATTGAAACTGTAACTTATGA CDS 21 1085 1973 OSL33 2187- 2187 TGCTACCAATCCGTGTAAAGATA CDS 21 1086 2209 OSL34 2437- 2437 TTCTTTGTCGGGATTGATTTTGA CDS 21 1087 2459 OSL35 2469- 2469 CAGCACTATCTTTTTTTCAGATA CDS 21 1088 2491 OSL36 2470- 2470 AGCACTATCTTTTTTTCAGATAT CDS 21 1089 2492 OSL37 2491- 2491 ATGTCAAAACACATGATTTTTAA CDS 21 1090 2513 OSL38 2498- 2498 AACACATGATTTTTAAGCAAAAG CDS 21 1091 2520 OSL39 2558- 2558 GGGTGGAAAATGTTGAAAGTTTG CDS 21 1092 2580 OSL40 2579- 2579 TGGCTTTTGATTGGATTTCAAAG CDS 21 1093 2601 OSL41 2580- 2580 GGCTTTTGATTGGATTTCAAAGA CDS 21 1094 2602 OSL42 2589- 2589 TTGGATTTCAAAGAATCTCTATT CDS 21 1095 2611 OSL43 2590- 2590 TGGATTTCAAAGAATCTCTATTG CDS 21 1096 2612 OSL44 2670- 2670 CACAGTAGTTCAGTATTTAAATA CDS 21 1097 2692 OSL45 2672- 2672 CAGTAGTTCAGTATTTAAATAAC CDS 21 1098 2694 OSL46 2714- 2714 ATCCTTTTGCCGGGTATCTATTC CDS 21 1099 2736 OSL47 2800- 2800 CCTGTAATAAACACTACTCTT CDS 21 1394 2820 OSL48 2869- 2869 TGGGTAGATGCCTATTTTGATAA CDS 21 1100 2891 OSL49 2877- 2877 TGCCTATTTTGATAAAATTGAGC CDS 21 1101 2899 OSL50 2971- 2971 GCCATCTTTGGAGAGCATTTATT CDS 21 1102 2993 OSL51 3074- 3074 TTGCTTACATACTGCATTTGAAA CDS 21 1103 3096 OSL52 3075- 3075 TGCTTACATACTGCATTTGAAAT CDS 21 1104 3097 OSL53 3120- 3120 TGGTTCTAACGCCTGTAATCAAC CDS 21 1105 3142 OSL54 3356- 3356 TCGATGATTGTCATGATAACAGT CDS 21 1106 3378 OSL55 3546- 3546 CACCCAATACACCTGTGATAATC CDS 21 1107 3568 OSL56 3547- 3547 ACCCAATACACCTGTGATAATCA CDS 21 1108 3569 OSL57 3569- 3569 ACCAGTGTATCTCAAAGAACTGG CDS 21 1109 3591 OSL58 3629- 3629 ATGAAAAGAACTGCAATTCGACA CDS 21 1110 3651 OSL59 3681- 3681 CCCCAATCATCGATGTATTGACC CDS 21 1111 3703 OSL60 3690- 3690 TCGATGTATTGACCTATCGTTTG CDS 21 1112 3712 OSL61 3693- 3693 ATGTATTGACCTATCGTTTGTCT CDS 21 1113 3715 OSL62 3828- 3828 TCGTTGTGATGGTGTTTTTGATT CDS 21 1114 3850 OSL63 3945- 3945 CCCGAACTTCTGGGAATGTGATG CDS 21 1115 3967 OSL64 3946- 3946 CCGAACTTCTGGGAATGTGATGG CDS 21 1116 3968 OSL65 4015- 4015 CCCAAGACTTGCCCTTCATCATA CDS 21 1117 4037 OSL66 4348- 4348 TTCTTACTTGCCAATGATTCTAA CDS 21 1118 4370 OSL67 4379- 4379 AAGACATAGATGAATGTGATATT CDS 21 1119 4401 OSL68 4381- 4381 GACATAGATGAATGTGATATTCT CDS 21 1120 4403 OSL69 4455- 4455 GTGTGATACAGGCTACATGTTAG CDS 21 1121 4477 OSL70 4464- 4464 AGGCTACATGTTAGAAAGTGATG CDS 21 1122 4486 OSL71 4465- 4465 GGCTACATGTTAGAAAGTGATGG CDS 21 1123 4487 OSL72 4597- 4597 GTCGAGAATGGTTCTTACATTGT CDS 21 1124 4619 OSL73 4600- 4600 GAGAATGGTTCTTACATTGTAGC CDS 21 1125 4622 OSL74 4612- 4612 TACATTGTAGCTGTTGATTTTGA CDS 21 1126 4634 OSL75 4620- 4620 AGCTGTTGATTTTGATTCAATTA CDS 21 1127 4642 OSL76 4622- 4622 CTGTTGATTTTGATTCAATTAGT CDS 21 1128 4644 OSL77 4635- 4635 TTCAATTAGTGGTCGTATCTTTT CDS 21 1129 4657 OSL78 4732- 4732 AGCATCATCTTGACTGAAACTAT CDS 21 1130 4754 OSL79 4735- 4735 ATCATCTTGACTGAAACTATTGC CDS 21 1131 4757 OSL80 4741- 4741 TTGACTGAAACTATTGCAATAGA CDS 21 1132 4763 OSL81 4743- 4743 GACTGAAACTATTGCAATAGATT CDS 21 1133 4765 OSL82 4745- 4745 CTGAAACTATTGCAATAGATTGG CDS 21 1134 4767 OSL83 4806- 4806 AACAATTGAAGTCTCCAAAATTG CDS 21 1135 4828 OSL84 4847- 4847 TGCTGATTAGTAAAAACCTAACA CDS 21 1136 4869 OSL85 4883- 4883 TAGCATTAGATCCCAGAATGAAT CDS 21 1137 4905 OSL86 4884- 4884 AGCATTAGATCCCAGAATGAATG CDS 21 1138 4906 OSL87 4896- 4896 CAGAATGAATGAGCATCTACTGT CDS 21 1139 4918 OSL88 5077- 5077 ATGGACTTTTGTGATTATAATGG CDS 21 1140 5099 OSL89 5080- 5080 GACTTTTGTGATTATAATGGACA CDS 21 1141 5102 OSL90 5126- 5126 GTGATTTGATTATACGGCA CDS 19 1142 5144 OSL91 5241- 5241 GTCAGTTGTAATGTATAATATTC CDS 21 1143 5263 OSL92 5246- 5246 TTGTAATGTATAATATTCAATGG CDS 21 1144 5268 OSL93 5291- 5291 ATCCTTCGAAACAACCAAATTCC CDS 21 1145 5313 OSL94 5295- 5295 TTCGAAACAACCAAATTCCGTGA CDS 21 1146 5317 OSL95 5447- 5447 AACCTTTCTTAATAACTGTAAGG CDS 21 1147 5469 OSL96 5467- 5467 AGGCAACATATAATTTTTGGAAT CDS 21 1148 5489 OSL97 5468- 5468 GGCAACATATAATTTTTGGAATC CDS 21 1149 5490 OSL98 5538- 5538 AGGGATACAGAATGGTTTAGATG CDS 21 1150 5560 OSL99 5539- 5539 GGGATACAGAATGGTTTAGATGT CDS 21 1151 5561 OSL100 5545- 5545 CAGAATGGTTTAGATGTTGAATT CDS 21 1152 5567 OSL101 5584- 5584 TACATCTATTGGGTTGAAAATCC CDS 21 1153 5606 OSL102 5644- 5644 AGGACAGTATTTGCTTCTATATC CDS 21 1154 5666 OSL103 5648- 5648 CAGTATTTGCTTCTATATCTATG CDS 21 1155 5670 OSL104 5677- 5677 CCTTCTATGAACCTGGCCTTA CDS 21 1156 5697 OSL105 5692- 5692 GCCTTAGATTGGATTTCAAGAAA CDS 21 1157 5714 OSL106 5701- 5701 TGGATTTCAAGAAACCTTTATTC CDS 21 1158 5723 OSL107 5738- 5738 CTCAGTCAATCGAGGTTTTGACA CDS 21 1159 5760 OSL108 5765- 5765 ACGGAGATATCAGATACAGAAAA CDS 21 1160 5787 OSL109 5766- 5766 CGGAGATATCAGATACAGAAAAA CDS 21 1161 5788 OSL110 5768- 5768 GAGATATCAGATACAGAAAAACA CDS 21 1162 5790 OSL111 5775- 5775 CAGATACAGAAAAACATTGATTG CDS 21 1163 5797 OSL112 6115- 6115 GTCCATGATTCTTTCCTTTATTA CDS 21 1164 6137 OSL113 6116- 6116 TCCATGATTCTTTCCTTTATTAT CDS 21 1165 6138 OSL114 6123- 6123 TTCTTTCCTTTATTATACTGATG CDS 21 1166 6145 OSL115 6146- 6146 AACAGTATGAGGTCATTGAAAGA CDS 21 1167 6168 OSL116 6202- 6202 TTGAGAGATAATGTTCCAAATCT CDS 21 1168 6224 OSL117 6204- 6204 GAGAGATAATGTTCCAAATCTGA CDS 21 1169 6226 OSL118 6206- 6206 GAGATAATGTTCCAAATCTGAGG CDS 21 1170 6228 OSL119 6266- 6266 CCTCAAATGGCTGTAGCAA CDS 19 1171 6284 OSL120 6387- 6387 CTCTCCATATAACTCTTTCATTG CDS 21 1172 6409 OSL121 6390- 6390 TCCATATAACTCTTTCATTGTTG CDS 21 1173 6412 OSL122 6397- 6397 AACTCTTTCATTGTTGTTTCAAT CDS 21 1174 6419 OSL123 6399- 6399 CTCTTTCATTGTTGTTTCAATGC CDS 21 1175 6421 OSL124 6425- 6425 CTGCAATCAGAGGCTTTAGCTTG CDS 21 1176 6447 OSL125 6426- 6426 TGCAATCAGAGGCTTTAGCTTGG CDS 21 1177 6448 OSL126 6434- 6434 GAGGCTTTAGCTTGGAATTGTCA CDS 21 1178 6456 OSL127 6436- 6436 GGCTTTAGCTTGGAATTGTCAGA CDS 21 1179 6458 OSL128 6445- 6445 TTGGAATTGTCAGATCATTCAGA CDS 21 1180 6467 OSL129 6603- 6603 TGGATCTTCTCTGATGAACATTG CDS 21 1181 6625 OSL130 6619- 6619 AACATTGTGACACATGGAATAGG CDS 21 1182 6641 OSL131 6711- 6711 TTCTGAAACACTGATAGAAGTTC CDS 21 1183 6733 OSL132 6725- 6725 TAGAAGTTCTGCGGATCAATACT CDS 21 1184 6747 OSL133 6797- 6797 TTGTTGTAGATCCCAAGAACAGA CDS 21 1185 6819 OSL134 6849- 6849 ACCAAAGATTGAGCGTTCTTTCC CDS 21 1186 6871 OSL135 6939- 6939 CCGAAGTGATGGCTACGTTTATT CDS 21 1187 6961 OSL136 6961- 6961 TGGGTTGATGATTCTTTAGATAT CDS 21 1188 6983 OSL137 6965- 6965 TTGATGATTCTTTAGATATAATT CDS 21 1189 6987 OSL138 7062- 7062 CACTGTTTTTGAAAATTCTATCA CDS 21 1190 7084 OSL139 7064- 7064 CTGTTTTTGAAAATTCTATCATA CDS 21 1191 7086 OSL140 7087- 7087 TGGGTAGATAGGAATTTGAAAAA CDS 21 1192 7109 OSL141 7088- 7088 GGGTAGATAGGAATTTGAAAAAG CDS 21 1193 7110 OSL142 7152- 7152 CACAGTGATAAGAGACAATATCA CDS 21 1194 7174 OSL143 7154- 7154 CAGTGATAAGAGACAATATCAAC CDS 21 1195 7176 OSL144 7348- 7348 GGCAAGAATTGTGCCATTTCAAC CDS 21 1196 7370 OSL145 7351- 7351 AAGAATTGTGCCATTTCAACAGA CDS 21 1197 7373 OSL146 7358- 7358 GTGCCATTTCAACAGAAAATTTC CDS 21 1198 7380 OSL147 7359- 7359 TGCCATTTCAACAGAAAATTTCC CDS 21 1199 7381 OSL148 7381- 7381 CTCATCTTTGCCTTGTCTAATTC CDS 21 1200 7403 OSL149 7443- 7443 ACCTTTCCAAACAATAAATGTGG CDS 21 1201 7465 OSL150 7486- 7486 GACTATGACAGTGTAAGTGATAG CDS 21 1202 7508 OSL151 7494- 7494 CAGTGTAAGTGATAGAATCTACT CDS 21 1203 7516 OSL152 7496- 7496 GTGTAAGTGATAGAATCTACTTC CDS 21 1204 7518 OSL153 7506- 7506 TAGAATCTACTTCACACAAAATT CDS 21 1205 7528 OSL154 7510- 7510 ATCTACTTCACACAAAATTTAGC CDS 21 1206 7532 OSL155 7627- 7627 GCCTTTGACTGGATTACTAGAAG CDS 21 1207 7649 OSL156 7633- 7633 GACTGGATTACTAGAAGAATTTA CDS 21 1208 7655 OSL157 7635- 7635 CTGGATTACTAGAAGAATTTATT CDS 21 1209 7657 OSL158 7636- 7636 TGGATTACTAGAAGAATTTATTA CDS 21 1210 7658 OSL159 8007- 8007 GACTCTCTATGGCCAGTATATTT CDS 21 1211 8029 OSL160 8036- 8036 CTGACTTGTACACACAAAGAATT CDS 21 1212 8058 OSL161 8038- 8038 GACTTGTACACACAAAGAATTTA CDS 21 1213 8060 OSL162 8044- 8044 TACACACAAAGAATTTACCGAGC CDS 21 1214 8066 OSL163 8150- 8150 ACCAGAAACAACAGTGTAACAAT CDS 21 1215 8172 OSL164 8152- 8152 CAGAAACAACAGTGTAACAATCC CDS 21 1216 8174 OSL165 8167- 8167 AACAATCCTTGTGAACAGTTTAA CDS 21 1217 8189 OSL166 8293- 8293 GTGGACAATGGTGAACGATGTGG CDS 21 1218 8315 OSL167 8564- 8564 CGGAGTTTATGTGCAATAACAGA CDS 21 1219 8586 OSL168 8566- 8566 GAGTTTATGTGCAATAACAGAAG CDS 21 1220 8588 OSL169 8685- 8685 TGGATACACAAAATGTCATAATT CDS 21 1221 8707 OSL170 8689- 8689 TACACAAAATGTCATAATTCAAA CDS 21 1222 8711 OSL171 8691- 8691 CACAAAATGTCATAATTCAAATA CDS 21 1223 8713 OSL172 8699- 8699 GTCATAATTCAAATATTTGTATT CDS 21 1224 8721 OSL173 8715- 8715 TTGTATTCCTCGCGTTTATTTGT CDS 21 1225 8737 OSL174 8768- 8768 GTGATGAAAACCCTACTTATTGC CDS 21 1226 8790 OSL175 8844- 8844 TCCTCAACATTGGTATTGTGATC CDS 21 1227 8866 OSL176 8854- 8854 TGGTATTGTGATCAAGAAACAGA CDS 21 1228 8876 OSL177 8861- 8861 GTGATCAAGAAACAGATTGTTTT CDS 21 1229 8883 OSL178 9063- 9063 TTCCGAGTTTCTCTGTGTAAATG CDS 21 1230 9085 OSL179 9064- 9064 TCCGAGTTTCTCTGTGTAAATGA CDS 21 1231 9086 OSL180 9153- 9153 CGGCTACGATGAGAATCAGAATT CDS 21 1232 9175 OSL181 9181- 9181 AGGAGAACTTGCTCTGAAAATGA CDS 21 1233 9203 OSL182 9221- 9221 GACTGTGTATCCCAAAGATATTC CDS 21 1234 9243 OSL183 9308- 9308 GCCAACAGAATCAGTTTACCTGT CDS 21 1235 9330 OSL184 9595- 9595 GACACCTTAACCAGTTTCTATTG CDS 21 1236 9617 OSL185 9598- 9598 ACCTTAACCAGTTTCTATTGTTC CDS 21 1237 9620 OSL186 9657- 9657 GACTTGTGTTGATATTGATGAAT CDS 21 1238 9679 OSL187 9719- 9719 ATGTAATAGGCTCCTACATCTGT CDS 21 1239 9741 OSL188 9786- 9786 CCGGCAAAACAGTAACATCGAAC CDS 21 1240 9808 OSL189 9807- 9807 ACCCTATCTCATTTTTAGCAACC CDS 21 1241 9829 OSL190 9826- 9826 AACCGTTACTATTTGAGAAATTT CDS 21 1242 9848 OSL191 9827- 9827 ACCGTTACTATTTGAGAAATTTA CDS 21 1243 9849 OSL192 9828- 9828 CCGTTACTATTTGAGAAATTTAA CDS 21 1244 9850 OSL193 9832- 9832 TACTATTTGAGAAATTTAACTAT CDS 21 1245 9854 OSL194 9838- 9838 TTGAGAAATTTAACTATAGATGG CDS 21 1246 9860 OSL195 9849- 9849 AACTATAGATGGCTATTTTTACT CDS 21 1247 9871 OSL196 9892- 9892 GACAATGTTGTGGCATTAGATTT CDS 21 1248 9914 OSL197 9925- 9925 GAGAAGAGATTGTATTGGATTGA CDS 21 1249 9947 OSL198 9956- 9956 GGCAAGTCATTGAGAGAATGTTT CDS 21 1250 9978 OSL199 9987- 9987 GACAAACAAGGAGACAATCATAA CDS 21 1251 10009 OSL200 10272- 10272 AACCAACAAGTCTGTGATAATCT CDS 21 1252 10294 OSL201 10444- 10444 TTCGCTATTACCATTTTTGAAGA CDS 21 1253 10466 OSL202 10446- 10446 CGCTATTACCATTTTTGAAGACA CDS 21 1254 10468 OSL203 10499- 10499 CAGTGGAAAAGGGAAACAAATAT CDS 21 1255 10521 OSL204 10513- 10513 AACAAATATGATGGATCAAATAG CDS 21 1256 10535 OSL205 10574- 10574 TCCATGTGTACCATCCATATAGG CDS 21 1257 10596 OSL206 10958- 10958 CTGATGAAGACCGTCTTCTTTGT CDS 21 1258 10980 OSL207 11246- 11246 GTGACAACTTCACAGAATTCAGC CDS 21 1259 11268 OSL208 11623- 11623 CAGTGTACAAGTGGACATTGTGT CDS 21 1260 11645 OSL209 11625- 11625 GTGTACAAGTGGACATTGTGTAC CDS 21 1261 11647 OSL210 11745- 11745 TACTATGTTCGAATGCAAAAACC CDS 21 1262 11767 OSL211 11749- 11749 ATGTTCGAATGCAAAAACCATGT CDS 21 1263 11771 OSL212 11757- 11757 ATGCAAAAACCATGTTTGTATCC CDS 21 1264 11779 OSL213 11779- 11779 CCGCCATATTGGAAATGTGATGG CDS 21 1265 11801 OSL214 11820- 11820 TGGTTCAGATGAAGAACTTCACC CDS 21 1266 11842 OSL215 11887- 11887 GACAACAATCGCTGCATTTATAG CDS 21 1267 11909 OSL216 11984- 11984 CCCCTAAACCTTGTACAGAATAT CDS 21 1268 12006 OSL217 11985- 11985 CCCTAAACCTTGTACAGAATATG CDS 21 1269 12007 OSL218 11990- 11990 AACCTTGTACAGAATATGAATAT CDS 21 1270 12012 OSL219 11991- 11991 ACCTTGTACAGAATATGAATATA CDS 21 1271 12013 OSL220 11994- 11994 TTGTACAGAATATGAATATAAGT CDS 21 1272 12016 OSL221 12083- 12083 CCGATGAACTGGGTTGCAATAAA CDS 21 1273 12105 OSL222 12114- 12114 AAGAACATGTGCTGAAAATATAT CDS 21 1274 12136 OSL223 12140- 12140 AGCAAAATTGTACCCAATTAAAT CDS 21 1275 12162 OSL224 12193- 12193 GGGTTCGAAACCAATGTTTTTGA CDS 21 1276 12215 OSL225 12197- 12197 TCGAAACCAATGTTTTTGACAGA CDS 21 1277 12219 OSL226 12389- 12389 CTGACAATGTCCGAATTCGAAAA CDS 21 1278 12411 OSL227 12397- 12397 GTCCGAATTCGAAAATATAATCT CDS 21 1279 12419 OSL228 12399- 12399 CCGAATTCGAAAATATAATCTCT CDS 21 1280 12421 OSL229 12435- 12435 CTCAGAGTATCTTCAAGATGAGG CDS 21 1281 12457 OSL230 12443- 12443 ATCTTCAAGATGAGGAATATATC CDS 21 1282 12465 OSL231 12537- 12537 GGGCTCTAGGTTTGGTGCTATCAAA CDS 25 1283 12561 OSL232 12564- 12564 TGCCTACATCCCCAACTTTGAAT CDS 21 1284 12586 OSL233 12608- 12608 AGGAAGTTGACCTGAAACTGAAA CDS 21 1285 12630 OSL234 12616- 12616 GACCTGAAACTGAAATACGTAAT CDS 21 1286 12638 OSL235 12617- 12617 ACCTGAAACTGAAATACGTAATG CDS 21 1287 12639 OSL236 12705 12705 ACGCATTGAGGTGGCTAAACTTG CDS 21 1288 12727 OSL237 12792- 12792 TCCCAAACTAGGGCTTATGTTCT CDS 21 1289 12814 OSL238 12825- 12825 GGGAAAGGAACCTAAAATCGAGT CDS 21 1290 12847 OSL239 12870- 12870 CCGCAACATCCTGGTTTTCGAGG CDS 21 1291 12892 OSL240 12911- 12911 GCCTTTCTATCGATTATTTGAAC CDS 21 1292 12933 OSL241 12915- 12915 TTCTATCGATTATTTGAACAATG CDS 21 1293 12937 OSL242 12965- 12965 AGGACGTTATTGAAACCATAAAA CDS 21 1294 12987 OSL243 12967 12967 GACGTTATTGAAACCATAAAATA CDS 21 1295 12989 OSL244 12968- 12968 ACGTTATTGAAACCATAAAATAT CDS 21 1296 12990 OSL245 12995- 12995 GGACTGATAGGAGAGTCATTGCAAA CDS 21 1297 13019 OSL246 13058- 13058 ACCAGTTATACTGGATATCTAAG CDS 25 1298 13080 OSL247 13086- 13086 GGGAGAAGTATGGAAACAAAATA CDS 21 1299 13108 OSL248 13091- 13091 AAGTATGGAAACAAAATAAATTT CDS 21 1300 13113 OSL249 13175- 13175 TTCATCAACTCAGATACAATAAG CDS 21 1301 13197 OSL250 13368- 13368 CGGAGGAAATTGCTATTTTGATG CDS 21 1302 13390 OSL251 13371- 13371 AGGAAATTGCTATTTTGATGAGA CDS 21 1303 13393 OSL252 13428- 13428 CACCGGAAAATATTGTGAAATGG CDS 21 1304 13450 OSL253 13440- 13440 TTGTGAAATGGCGTTTTCAAAAG CDS 21 1305 13462 OSL254 13541- 13541 CAGGATTCTTCCACTATAGAAGG CDS 21 1306 13563 OSL255 13659- 13659 GGCAGATCTTAACATGGATATTG CDS 21 1307 13681 OSL256 13725- 13725 GGCAATGAGTGAAGACTTTGTCA CDS 21 1308 13747 OSL257 13842- 13842 ATCTGAAAATGTGGATAATAAGA CDS 21 1309 13864 OSL258 13844- 13844 CTGAAAATGTGGATAATAAGAAT CDS 21 1310 13866 OSL259 13852- 13852 GTGGATAATAAGAATTATGGAAG CDS 21 1311 13874 OSL260 13853- 13853 TGGATAATAAGAATTATGGAAGT CDS 21 1312 13875 OSL261 13951- 13951 TGGAATCTCTTCAAACGAAAATC CDS 21 1313 13973 OSL262 13955- 13955 ATCTCTTCAAACGAAAATCTAAA CDS 21 1314 13977 OSL263 13957- 13957 CTCTTCAAACGAAAATCTAAACA CDS 21 1315 13979 OSL264 13960- 13960 TTCAAACGAAAATCTAAACAAAC CDS 21 1316 13982 OSL265 13964- 13964 AACGAAAATCTAAACAAACTACC CDS 21 1317 13986 OSL266 13976- 13976 AACAAACTACCAACTTTGAAAAT CDS 21 1318 13998 OSL267 13983- 13983 TACCAACTTTGAAAATCCAATCT CDS 21 1319 14005 OSL268 13987- 13987 AACTTTGAAAATCCAATCTATGC CDS 21 1320 14009 OSL269 14121- 14121 TGCAACAGAAGACACTTTTAAAG CDS 21 1321 14143 OSL270 14145- 14145 CACCGCAAATCTTGTTAAAGAAG CDS 21 1322 14167 OSL271 14148- 14148 CGCAAATCTTGTTAAAGAAGACT CDS 21 1323 14170 OSL272 14169- 14169 CTCTGAAGTATAGCTATACCAGC CDS/3- 21 1324 14191 UTR OSL273 14186- 14186 ACCAGCTATTTAGGGAATAATTA 3-UTR 21 1325 14208 OSL274 14188- 14188 CAGCTATTTAGGGAATAATTAGA 3-UTR 21 1326 14210 OSL275 14211- 14211 AACACACTTTTGCACATATATTT 3-UTR 21 1327 14233 OSL276 14213- 14213 CACACTTTTGCACATATATTTTT 3-UTR 21 1328 14235 OSL277 14236- 14236 TACAAACAGATGAAAAAAGTTAA 3-UTR 21 1329 14258 OSL278 14252- 14252 AAGTTAACATTCAGTACTTTATG 3-UTR 21 1330 14274 OSL279 14261- 14261 TTCAGTACTTTATGAAAAAAATA 3-UTR 21 1331 14283 OSL280 14263- 14263 CAGTACTTTATGAAAAAAATATA 3-UTR 21 1332 14285 OSL281 14341- 14341 CCGTCTCATATTTTTACAAATAA 3-UTR 21 1333 14363 OSL282 14355- 14355 TACAAATAATTATCACAATGTAC 3-UTR 21 1334 14377 OSL283 14366- 14366 ATCACAATGTACTATATGTATAT 3-UTR 21 1335 14388 OSL284 14368- 14368 CACAATGTACTATATGTATATCT 3-UTR 21 1336 14390 OSL285 14372- 14372 ATGTACTATATGTATATCTTTGC 3-UTR 21 1337 14394 OSL286 14396- 14396 CTGAAGTTGTCTGAAGGTAATAC 3-UTR 21 1338 14418 OSL287 14406- 14406 CTGAAGGTAATACTATAAATATA 3-UTR 21 1339 14428 OSL288 14437- 14437 TTGTAAATTTTGGAAAGATTATC 3-UTR 21 1340 14459 OSL289 14447- 14447 TGGAAAGATTATCCTGTTACTGA 3-UTR 21 1341 14469 OSL290 14451- 14451 AAGATTATCCTGTTACTGAATTT 3-UTR 21 1342 14473 OSL291 14457- 14457 ATCCTGTTACTGAATTTGCTAAT 3-UTR 21 1343 14479 OSL292 14458- 14458 TCCTGTTACTGAATTTGCTAATA 3-UTR 21 1344 14480 OSL293 14464- 14464 TACTGAATTTGCTAATAAAGATG 3-UTR 21 1345 14486 OSL294 14503- 14503 GTGATCATTATAGTAAATGATCC 3-UTR 21 1346 14525 OSL295 14513- 14513 TAGTAAATGATCCAACAAGAAAA 3-UTR 21 1347 14535 OSL296 14523- 14523 TCCAACAAGAAAAGGAATTGACT 3-UTR 21 1348 14545 OSL297 14579- 14579 CACTCATATTTCCTATAAAATTA 3-UTR 21 1349 14601 OSL298 14581. 14581 CTCATATTTCCTATAAAATTATC 3-UTR 21 1350 14603 OSL299 14633- 14633 GTCCATTTTTACACATTAGCACT 3-UTR 21 1351 14655 OSL300 14649- 14649 TAGCACTTAATTAATGTTCAATA 3-UTR 21 1352 14671 OSL301 14650- 14650 AGCACTTAATTAATGTTCAATAT 3-UTR 21 1353 14672 OSL302 14652- 14652 CACTTAATTAATGTTCAATATTA 3-UTR 21 1354 14674 OSL303 14665- 14665 TTCAATATTACATGTCAATTTGA 3-UTR 21 1355 14687 OSL304 14684- 14684 TTGATTAATGGCTATGTTGATAG 3-UTR 21 1356 14706 OSL305 14708- 14708 GGCCACTATGTGTTGTATAGACA 3-UTR 21 1357 14730 OSL306 14711- 14711 CACTATGTGTTGTATAGACATCT 3-UTR 21 1358 14733 OSL307 14767- 14767 AGGTAGGAAAAGCAATTCAGTTT 3-UTR 21 1359 14789 OSL308 14856- 14856 GCCAAGACAACATTTTTATTTGT 3-UTR 21 1360 14878 OSL309 14861- 14861 GACAACATTTTTATTTGTGATGT 3-UTR 21 1361 14883 OSL310 14886- 14886 ATGAGGAAATCCCATATCATTAA 3-UTR 21 1362 14908 OSL311 14921- 14921 TGCATTGAGTTTGTGGTTAATTA 3-UTR 21 1363 14943 OSL312 14925- 14925 TTGAGTTTGTGGTTAATTAAATG 3-UTR 21 1364 14947 OSL313 15034 15034 AGCTGAATTTCTGAAACCAAATC 3-UTR 21 1365 15056 OSL314 15049- 15049 ACCAAATCTGTGTCTTCATAAAA 3-UTR 21 1366 15071 OSL315 15115- 15115 TGGGTTTTTGTTTCTATGAAAAT 3-UTR 21 1367 15137 OSL316 15122- 15122 TTGTTTCTATGAAAATATCATTA 3-UTR 21 1368 15144 OSL317 15126- 15126 TTCTATGAAAATATCATTATAAT 3-UTR 21 1369 15148 OSL318 15130- 15130 ATGAAAATATCATTATAATCACT 3-UTR 21 1370 15152 OSL319 15138- 15138 ATCATTATAATCACTATTTATTT 3-UTR 21 1371 15160 OSL320 15188- 15188 AACCATTCTTATTAAGCTTTTTA 3-UTR 21 1372 15210 OSL321 15189- 15189 ACCATTCTTATTAAGCTTTTTAT 3-UTR 21 1373 15211 OSL322 15220- 15220 GTGGCTAAATGTGTACATTTATA 3-UTR 21 1374 15242 OSL323 15221- 15221 TGGCTAAATGTGTACATTTATAT 3-UTR 21 1375 15243 OSL324 15222- 15222 GGCTAAATGTGTACATTTATATT 3-UTR 21 1376 15244 OSL325 15228- 15228 ATGTGTACATTTATATTAGAATG 3-UTR 21 1377 15250 OSL326 15263- 15263 CAGATCTTTTCTTTAATTCTTAT 3-UTR 21 1378 15285 OSL327 15266- 15266 ATCTTTTCTTTAATTCTTATTGG 3-UTR 21 1379 15288 OSL328 15271- 15271 TTCTTTAATTCTTATTGGTTTTT 3-UTR 21 1380 15293 OSL329 15438- 15438 CTCTTAAATAGTGGGTATAGTCT 3-UTR 21 1381 15460 OSL330 15524- 15524 GTGCTAATATTGCACATTTGTTA 3-UTR 21 1382 15546 OSL331 15525- 15525 TGCTAATATTGCACATTTGTTAA 3-UTR 21 1383 15547 OSL332 15575- 15575 ATGGATGAATGAATGAAACATAT 3-UTR 21 1384 15597 OSL333 15583- 15583 ATGAATGAAACATATACTACTGA 3-UTR 21 1385 15605 OSL334 15587- 15587 ATGAAACATATACTACTGATTAT 3-UTR 21 1386 15609 OSL335 15591- 15591 AACATATACTACTGATTATTTTA 3-UTR 21 1387 15613 OSL336 15655- 15655 CTGACTGTAATTACTTTGATTAG 3-UTR 21 1388 15677 OSL337 15659- 15659 CTGTAATTACTTTGATTAGATAA 3-UTR 21 1389 15681 OSL338 15675- 15675 TAGATAAACAACTGGAAATAATG 3-UTR 21 1390 15697 OSL339 15698- 15698 CTGCTGAAAAAGTTCTAATAAAT 3-UTR 21 1391 15720 OSL340 15699- 15699 TGCTGAAAAAGTTCTAATAAATG 3-UTR 21 1392 15721

TABLE-US-00021 TABLE11 AdditionaltableofsiRNAsequences SEQ antisensesequence sensesequence SEQID ID OSID (5to3) OSID (3to5) NO:S 957 OSC17C-1 CAGUUGCGCAGUUUCUUGUC OSC17B-1 [dT][dT]GUCAACGCGUCA 973 AGUUC[dT][dT] AAGAACAGUCAAG 958 OSC17C-2 CAGUUGCGCAGUUUCUUGU OSC17B-2 [dT][dT]*G*UCAACGCGUC 974 [mC][mA]GUUC[dT][dT] AAAGAACAGUCAAG 959 OSC17C-3 CAGUUGCGCAGUUUCU[mU] OSC17B-3 [dT][dT]*G*UCAACGCGUC 975 [mG]UCAGUUC[dT][dT] AAAGAACAG[mU]CAAG 960 OSC17C-4 CAGUUGCGCAGUUUCU[mU] OSC17B-4 [dT][dT]*G*UCAACGCGUC 976 [mG]U[mC][mA]GUUC[dT] AAAGAA[mC]AGUCAAG [dT] OSC17B-5 [dT][dT]*G*UCAACGCGUC 977 AAAGAA[mC]AG[mU]CAA G OSC17B-6 [dT][dT]*G*UCAA[mC]GCG 978 UCAAAGAA[mC]AG[mU]C AAG 961 OSC47C-1 AAGAGCUCAGGUCUCUGAGG OSC47B-1 [dT][dT]UUCUCGAGUCCA 979 G[dT][dT] GAGACUCCC 962 OSC47C-2 AAGAGCUCAGGUCUC[mU]GA OSC47B-2 [dT][dT]*U*UCUCGAGUCC 980 GGG[dT][dT] AGAGACUCCC 963 OSC47C-3 AAGAGCUCAGGUCUC[mU][mG] OSC47B-3 [dT][dT]*U*UCUCGAGUCC 981 AGGG[dT][dT] AGAGA[mC]UCCC OSC47B-4 [dT][dT]*U*UCUCGAGUCC 982 AGAG[mA][mC]UCCC OSC47B-5 [dT][dT]*U*UCUCGAG[mU] 983 CCAGAG[mA][mC]UCCC 964 OSL231C-1 UUUGAUAGCACCAAACCUAGA OSL231B-1 [dT][dT]AAACUAUCGUGG 984 GCCC[dT][dT] UUUGGAUCUCGGG 965 OSL231C-2 UUUGA[mU]AG[mC]ACCAAACC OSL231B-2 [dT][dT]*A*AACUAUCGUG 985 [mU]AGAGCCC[dT][dT] GUUUGGAUCUCGGG 966 OSL231C-3 UUUGAUAGCACCAAACC[mU] OSL231B-3 [dT][dT]*A*AACUA[mU]CG 986 [mA]GAGCCC[dT][dT] [mU]GGUUUGGA[mU]CUC GGG 967 OSL231C-4 UUUGAUAG[mC]ACCAAACC OSL231B-4 [dT][dT]*A*AACU[mA][mU] 987 [mU]AGAGCCC[dT][dT] C[mG][mU]GGUUUGG[mA] [mU]CUCGGG 968 OSL231C-5 UUUGAUAGCACCAAACC[mU]A OSL231B-5 [dT][dT]*A*AACUGUCGUG 988 GAGCCC[dT][dT] GUUUGGA[mU]CUCGGG OSL231B-6 [dT][dT]*A*AACUGUCG 989 [mU]GGUUUGGA[mU]CUCG GG OSL231B-7 [dT][dT]*A*AACUAUCGUG 990 G[mU]UUGGAUCUCGGG 969 OSL245C-1 UUUGCAAUGACUCUCCUAUCA OSL245B-1 [dT][dT]AAACGUUACUGA 991 GUCC[dT][dT] GAGGAUAGUCAGG 970 OSL245C-2 UUUGCAA[mU][mG]ACUCUCC OSL245B-2 [dT][dT]*A*AACG[mU]UA 992 [mU][mA]UCAGUCC[dT][dT] [mC]UGAGAGGA[mU]AGUC AGG 971 OSL245C-3 UUUGCAAUGACUCUCC[mU] OSL245B-3 [dT][dT]*A*AACGUUACUG 993 [mA]UCAGUCC[dT][dT] AGAGGA[mU]AGUCAGG 972 OSL245C-4 UUUGCAA[mU][mG]ACUCUCCU OSL245B-4 [dT][dT]*A*AACGUUA[mC] 994 AUCAGUCC[dT][dT] UGAGAGGA[mU]AGUCAG G OSL245B-5 [dT][dT]*A*AACGUUACUG 995 AGAGGAUAGUCAGG Key to modifications [dT]=DNA base (T) within RNA oligo [mA], [mG], [mC], [mU]=2O-Methyl RNA * =Phosphorothioate linkages

[0170] In one embodiment, an RNAi (e.g., a dsRNA) featured herein includes a first sequence of a dsRNA that is selected from the group including the sense sequences of any table herein and a second sequence that is selected from the group consisting of the corresponding antisense sequences of any table herein. A corresponding antisense sequence is a nucleotide sequence within the OSID family for example OSC17. In those instances when we refer to an siRNA with no suffix (e.g., OSC17), we mean that to indicate the dsRNA comprised of the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC17S or OSC17C-(n) paired with OSC17B-(n) where n is any number of the OSC17 family).

[0171] Unless otherwise specified, the compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. It is understood that the phosphorothioate group, designated by an asterisk (*), constitutes a stereogenic center, and the presence of each such group in a sequence engenders two diastereoisomers. The number of such diastereoisomers in a double stranded RNAi agent may be calculated by the formula 2{circumflex over ()}n, wherein n represents the number of phosphorothioate groups in a sequence comprised of a double stranded siRNA.

[0172] In some embodiments, the antisense strand (identified with A in the OS ID name) and/or the sense strand (identified with S in the OS ID name) of an RNAi agent comprises or consists of a nucleobase sequence, for example, OSC17A-1 CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), and the nucleobase sequence may include at least one or more nucleotides as a modified nucleotide, and wherein SEQ ID NO: 17 is located at positions 1 to 25 (5.fwdarw.3) of the antisense strand and forms a duplex with the corresponding sense strand (identified as OSC17S-1. In some embodiments, the antisense strand of an RNAi agent comprises or consists of a nucleobase sequence for example CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), wherein all or substantially all or 1, 2, 3, 4 or 5 of the nucleotides are modified nucleotides (see for example SEQ ID NO. 24), and wherein SEQ ID NO: 24 is located at positions 1 to 27 (5.fwdarw.3) of the antisense strand. For any antisense or sense strand disclosed herein, in some embodiments, the antisense strand of an RNAi agent comprises or consists of the sequence (5.fwdarw.3) wherein * is a phosphorothioate linkage between deoxy thymine [dT]; and/or wherein mC, mA, mG, mU are 2-O-methyl cytidine, 2-O-methyl adenine, 2-O-methyl guanosine, 2-O-methyl uridine respectively; and/or wherein 2fA, 2fU, 2fG, 2fC are 2-fluoro adenine, 2-fluoro uridine, 2-fluoro guanosine, and 2-fluoro cytosine respectively. The antisense target on the mRNA is identified with the same name but without the notation of A or S after the name. An antisense sequence with the same name, for example OSC17A-1 through OSC17A-18 binds to the same nucleotide target sequence.

[0173] Sequences shown in Table 4 were transfected into HEK 293 (human embryonic kidney) and MDA-MB-435S (human melanoma) cell lines to determine their ability to reduce the protein expression of LRP2 and CD320 gene/protein. These two cell lines were chosen because of their relatively high expression levels of LRP2 as noted in the Human Protein Atlas at world wide web.proteinatlas.org and the NCI-60 gene expression profiles at discover.nci.nih.gov/cellminer/so that a change in protein expression for LRP2 was easy to detect.

[0174] Referring now to FIGS. 3A-B and FIG. 3D-E, HEK293 and MDA-MB-231 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs represent the fold change of protein levels compared to the scrambled siRNA control (OSS1). (Average/+SEM is shown, n=3).

[0175] CD320 and LRP2 protein levels were determined by western blot and quantified by Image Studio Software (LiCor Company), relative to a control protein that is not affected by CD320 or LRP2 knockdown. To determine the efficacy of knockdown, protein levels of CD320 (FIGS. 3A-B) and LRP2 (FIGS. 3 D-E) on the samples that were exposed to siRNA sequences against the mRNA of either gene, were compared to that in the untreated and scrambled controls (black and gray bars, respectively, in all graphs of FIG. 3). We found that both siRNA sequences directed against CD320 (OSC17 and OSC47) almost completely abrogated CD320 expression (circles in FIG. 3A-B). siLRP2 sequences resulted in variable efficiency in reducing LRP2 protein. Two sequences (OSL231 and OSL245) consistently reduced LRP2 levels 75% or more in both cell lines (circles FIGS. 3 B, E).

[0176] Referring now to FIG. 6, lysates were made from transformed (HEK293) and representative cancer cell lines, and western blot was performed to determine LRP2 protein levels. The cancer cells screened have low levels of LRP2 expression. The results represent the averages+SEM of three independent lysates. The data suggests that the cancer cells screened have very low levels of LRP2 expression.

[0177] We transfected a panel of LRP2 and CD320 siRNAs into cancer cell lines derived from multiple tissues and analyzed the levels of LRP2 protein and CD320 protein in the cell line. Representative cell lines from prostate, breast and glioblastoma, and normal fibroblasts were exposed to CD320 and LRP2 siRNAs in an experimental set-up similar to that described for HEK293 and MDA-MB-435S cells. The results are shown in FIGS. 3 C, F, and FIG. 4.

[0178] Referring now to FIGS. 3 C, F; and FIG. 4, MDA-MB-231 LnCAP, MCF-7 and U251 cells were exposed to siRNA sequences to knockdown CD320 (FIG. 3C, and FIGS. 4A-C) and LRP2 (FIG. 3 F, and FIGS. 4 D-F), in a similar fashion as described for the data represented in FIGS. 3A, B, D, and E. CD320 protein knockdown FIG. 3C, and FIG. 4A-C, compared to the untreated or scrambled controls, is more than 90% for all cell lines tested. LRP2 knockdown is accomplished in all cell lines too. However, the level of knockdown is less in the LnCAP cells compared to the other cell lines and the sequences that are effective may differ as well (FIG. 3 F, and FIGS. 4 D-F).

[0179] Referring now to FIG. 5, an experimental set up similar to that described in FIG. 3 was employed. Additional prostate and brain cancer cell lines, as well as normal fibroblast, were exposed to siRNAs directed against CD320. Levels of CD320 were nearly abrogated in DU-145 (prostate) cells, whereas the levels of knockdown in A172 brain cells and normal fibroblasts were 21%-33% and 25%-28%, respectively (FIG. 5A-C).

[0180] From these studies we can conclude that two siRNAs to CD320 (OSC17 and OSC47) are very effective in knocking down CD320 protein levels (80% or more), in nearly every cell line tested. While LRP2 is theoretically harder to knock down because of its size, we have identified two siRNAs, OSL231 and OSL245, that consistently knock down LRP2 in most cell lines in which we can detect LRP2.

[0181] In addition, LRP2 protein expression levels are very high in HEK 293 cells and easily detectable by western blot. Cancer cell lines have much lower expression of LRP2 compared to HEK293 cells as measured by western blot (FIG. 6), and some cell lines may contain LRP2 at levels below reliable detection.

[0182] Referring now to FIG. 7, the effects of doxorubicin treatment on cell viability, as measured by the CTG assay, are illustrated. A172 and HCC15 cells were plated at 1200 cells/well in a 96 well plate. The next day, cells were treated with doxorubicin at the indicated concentrations. Four days after the doxorubicin exposure was initiated, the cells were assayed for viability using the CTG assay. The line indicates the non-linear fitting of the data to calculate an IC.sub.50 value. Instead of visually assessing the effect of CD320/LRP2 gene expression knockdown on cell proliferation (as shown for shRNA-mediated CD320/LRP2 knockdown in FIG. 2), a functional assay for quantitating the effect on cell viability of the simultaneous knockdown of LRP2 and CD320 by siRNA was developed. A widely used assay for the measurement of cell viability is the Promega Cell-titer GLO platform (CTG), which quantifies ATP levels in the cell (live cells produce ATP, dead cells do not). After incubating the cells with the CTG reagent, ATP levels can be indirectly measured as light production using the TECAN luminescence plate reader. As a first step, toxicity of a known chemotherapeutic drug, doxorubicin, was assayed on the cell lines of interest. Doxorubicin was used as a positive control for cell toxicity in our assay. Representative data from A172 brain cancer cells (FIG. 7A) and HCC15 lung cancer cells (FIG. 7B) exposed to doxorubicin are shown in FIG. 7. From this data, the IC.sub.50 of doxorubicin treatment on these cell lines was determined: 132 nm for A172 cells and 167 nm for HCC15 cells. Based upon these findings, a larger screen was initiated to determine the IC.sub.50 of doxorubicin in several cancer and non-cancer cell lines, to determine the doxorubicin dose to use when cell lines are used in the viability assay to test the simultaneous knockdown of CD320 and LRP2. The results of the cell lines tested are summarized in Table 8 IC.sub.50 determination of doxorubicin.

[0183] To quantify the effects of knocking down CD320 and LRP2 on cell proliferation, cells are plated in a 24-well plate. The next day, the cells are transfected with siRNAs to CD320 and/or LRP2. The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. At the end of the study, the cell lines are analyzed for cell growth by the CTG assay. A schematic of this experimental setup is presented in FIG. 8.

TABLE-US-00022 TABLE 8 Cancer type Cell line IC.sub.50 (nM) Glioblastoma A172 132 U251 24 Breast MDA-MB-231 43 MCF7 121 Prostate DU145 248 PC3 387 Lung NCI-H460 56 A549 126 HCC15 167 Melanoma MDA-MB-435S 325 Other GM05659 267 HEK293 29

[0184] The cells lines were plated at 1,000 to 4,000 cells/well in a 96-well plate and treated with doxorubicin the following day. CTG activity was measured 4 days after treatment. IC.sub.50 values were calculated by GraphPad Prism Software. Results are tabulated in Table 8.

[0185] These data show that doxorubicin works efficiently on this CTG platform (i.e., doxorubicin kills cancer cells) and can thus be used as a positive control in the in vitro assay to compare the cytotoxic effects of siRNA-knockdown of CD320 and LRP2. In this latter assay, normal or cancer cells are transfected with individual or combinations of siRNAs sequences that are targeting CD320 or LRP2 specifically or control siRNAs, similar to the experiments that provided the data for FIGS. 3, 4, and 5. In FIGS. 3, 4, and 5, protein levels are measured, but in the in vitro assay, cell viability is measured.

[0186] Referring now to FIG. 8, an overview of a functional assay for screening (ds) siRNA effects on cell proliferation is illustrated. To quantify the effects of knocking down CD320 and LRP2 on cell proliferation, cells are plated in a 24-well plate. The next day, the cells are transfected with siRNAs to CD320 and/or LRP2. The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. At the end of the study, the cell lines were analyzed for cell growth by the CTG assay.

[0187] Now, referring to FIG. 10B, MDA-MB-231 triple negative breast cancer cells were plated in a 24-well plate at 20,000 cells/well. Cells were transfected the next day with an siRNA selected from the group of OSC17, OSC47, OSL231, and OSL245 at 20 nM. Cells were also transfected with combinations of two siRNAs each of 10 nM, one of these targeting CD320 and the other LRP2, with the siRNAs targeting CD320 selected from the group of OSC17 and OSC47, and the LRP2 targeting siRNAs selected from the group of OSL231 and OSL245, each dosed at 10 nM. Cells were repeated transfected 4 times over the course of 11 days as indicated in Table 9. At day 11, cells were analyzed for cell growth by the CTG assay. The percent cell survival compared to the non-targeting control (OSS2) is shown. The data represented is the average of 6 experiments/+SEM.

[0188] Now, referring to FIG. 11, MDA-MB-231 and DU-145 cells were transfected with 20 nM of the negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA targeting LRP2 (OSL245). Cells were also transfected with a combination of a CD320 targeting siRNA (OSC17) and LRP2 targeting siRNA (OSL24), over a range of concentrations (2-20 nM), so the concentration of the two siRNAs equaled 20 nM total siRNA transfected, as indicated in FIG. 11. Cells were repeatedly transfected as indicated in Table 9, and the percent cell survival is shown.

[0189] Now, referring to FIG. 12, MDA-MB-231 breast cancer cells were transfected with 20 nM of the negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA targeting LRP2 (OSL245). Each day, over five days, lysates were prepared. Western blotting was performed on the lysates for CD320 protein levels (FIG. 12A) or LRP2 protein levels (FIG. 12B).

[0190] Referring now to FIG. 9 and FIG. 10, data quantifying the effects of knocking down CD320 and LRP2 in various cell lines is represented. Cell lines representative of several types of cancers or normal fibroblasts were transfected with individual or combinations of siRNAs to CD320 or LRP2 as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin treated cells served as a positive control for cell toxicity in our assays.

[0191] The data of the individual experiments presented in FIG. 9 and FIG. 10 and additional cell lines we have screened are summarized in Table 9. These experiments show the broad applicability of siCD320 and siLRP2 toxicity in a variety of cancer types.

[0192] Referring now to FIG. 13, a schematic of PEI and siRNA complexes is illustrated. PEI and siRNAs are mixed together. Subsequently, polyplexes (a nanoparticle, broadly speaking) form of the PEI-siRNA complex, which are able to enter the cell via an endocytotic or pinocytotic mechanism.

[0193] Referring now to FIG. 14, siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the sequence of the siRNA is complementary to a mRNA expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are unwound via the RISC (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity. The end result is that the mRNA targeted by the siRNA is degraded, and the protein encoded by the mRNA is not produced. This causes the knockdown effect or reduced protein levels of the gene targeted by the siRNA compared to control-treated cells.

[0194] Referring now to FIG. 15 effectiveness of INTERFERin in delivering siRNAs to cancer cells is illustrated. 2 nM of indicated siRNAs were transfected into A172 and MDA-MB-435S cells as per the manufacturers protocol. Cell lysates were prepared 3 days post-infection and analyzed by western blot for CD320 protein levels. OSS1 and OSS2 are non-targeting siRNA controls. In this experiment, both sequences were tested. CD320 protein levels were knocked down to 9% to 18% for A172 cells and 26% to 48% for MDA-MB-435S cells, compared to OSS1. Much more efficient knockdown of CD320 is observed when the siRNAs were delivered with other transfection reagents (e.g. RNAiMAX, Viromer Blue) that were used in the experiments described previously particularly for MDA-MB-435S cells. The Polyplus INTERFERin platform has been tested in vitro in our laboratory in a proof of principle experiment, whereby the platform is able to deliver siRNAs to the target cells in vitro.

[0195] Referring now to FIG. 16, treatment of breast, prostate, and skin cancer cells with an inhibitor of CD320 receptor or an inhibitor of LRP2 receptor or a combination of both in an amount effective to inhibit proliferation of the cancer cells as compared to the control cells treated with control SiRNA is illustrated. MDA-MB-231, DU145, LnCAP, and MDA-MB-435S cells were plated at 20,000 cells per well in a 24-well plate. The next day, the cells were transected with 20 nM of indicated siRNAs to knock down CD320, LRP2, or scrambled control. For the combination of siRNAs, cells were treated with 10 nM of each siRNA for 20 nM total treatments. Cells were repeatedly transfected as in Table 9 for the length of time indicated in Table 9. The indicated pictures of the cells were taken at the end of the experiment.

TABLE-US-00023 TABLE 9 Summary of functional siRNA data screening Single siRNA Double siRNA knockdown knockdown (siCD320) (siLRP2) OSC17+ OSC47+ # of Days OSC- OSO- OSL- OSL- OSL OSL OSL OSL Cell line n txns expt 17 47 231 245 231 245 231 245 DOX Normal GM05659 3 4 7 133 104 96 103 111 129 97 107 39 Lung HCC15 3 2 7 86 109 68 92 81 93 38 105 2 H157 3 5 8 7 9 116 33 119 39 31 15 20 Melanoma MDA-MB-435S 4 5 10 119 108 92 31 122 56 103 70 51 Prostate LnCAP 3 4 7 52 42 72 60 68 51 52 57 38 DU-145 6 4 7 39 82 71 44 80 44 90 76 40 Glioblastoma A172 3 5 7 94 17 50 101 73 107 19 51 8 U251 4 6 8 94 50 77 97 99 94 66 87 51 Breast MCF-7 3 2 7 61 69 32 68 31 52 26 48 5 MDA-MB-231 6 4 11 66 81 130 77 71 44 81 61 7 Note: The numbers represent percent survival compared to negative control OSS2.

[0196] A murine human tumor xenograft model was established using triple-negative breast cancer cells (MDA-MB-231) injected into the flanks of nude mice to test the efficacy of combined dosing of OSC17 and OSL245. The administration of the drug is by repeated dosing over a range of drug concentrations using intratumoral, iv, ip or specialized route of administration. The dosing schedule is based on pilot studies to determine the tolerability of the delivery vehicle and the drug and will incorporate ranges that are taught in the art. Among the delivery platforms are nanoparticles, liposomes, micelles, polymers, small molecule conjugates, aptamers and antibody conjugates. Hybrid technologies containing elements of the aforementioned delivery systems are also known.

[0197] The manufacturing process consists of synthesizing the two single strand oligonucleotides of the duplex by conventional solid phase oligonucleotide synthesis. After purification, the two oligonucleotides are annealed into the duplex.

[0198] In vivo JetPEI is a cationic polymer delivery system that binds the negatively charged siRNA molecules to the cationic polyamine polymer. Its use has been reported in xenograft models using MCF-7 (breast), MDA-MB-231 (breast) and A549 (lung) cell lines both ip and intratumoral. This delivery system is currently used in seven human clinical trials (Table 10). The formulated siRNAs are reported to be very stable.

TABLE-US-00024 TABLE 10 Clinical trial use of in vivo-jetPEI Organization Type of study Phase Cancer Targeting Systems Imaging and cancer Pre-clinical therapy Benitec Lung metastases Pre-clinical Avena Blood-brain barrier Pre-clinical BiOncoTech Melanoma immunotherapy Phase 1 Ottawa Hospital Research Acute myocardial infarction Phase 1 Institute gene therapy CHU-Toulouse, Rangueil Pancreatic cancer gene Phase 2 Hospital therapy BioCancell Bladder cancer gene Phase 3 therapy

[0199] Note that in the specification and claims, about or approximately means within twenty percent (20%) of the numerical amount cited. Although the invention has been described in detail with particular reference to these embodiments, other embodiments can achieve the same results. For example, antisense oligonucleotides that are complimentary to the target mRNA can inhibit expression of the protein of interest even though the antisense oligonucleotide is not provided as a dsRNA and may not bind to RISC/AGO complex. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above are hereby incorporated by reference.