The present invention relates, in general to agents that modulate the pharmacological activity of siRNAs. In addition, the invention relates generally to methods and systems for use in assessing the efficacy and safety of a pharmaceutical composition for use in the treatment or prophylaxis of a disease.

A modified oligonucleotide having an activity of inhibiting Ataxin 3 expression and having any one of the following nucleobase sequences or a nucleobase sequence of 17 contiguous bases contained in the nucleobase sequences:

TABLE-US-00001 (SEQ ID NO: 239) (1) TCGGGTAAGTAGATTTTC, (SEQ ID NO: 240) (2) GAAGTATCTGTAGGCCTA, (SEQ ID NO: 241) (3) GGACTGTATAGGAGATTA, (SEQ ID NO: 242) (4) GGTTATAGGATGCAGGTA, (SEQ ID NO: 243) (5) AGGTTATAGGATGCAGGT, (SEQ ID NO: 244) (6) GAAGCTAAGTAGGTGACT, (SEQ ID NO: 245) (7) TGAAGCTAAGTAGGTGAC, (SEQ ID NO: 246) (8) CCTAGTCACTTTGATAGA, (SEQ ID NO: 247) (9) GGAACATCTTGAGTAGGT, (SEQ ID NO: 248) (10) GGTGTTCAGGGTAGATGT, (SEQ ID NO: 249) (11) GGATACTCTGCCCTGTTC, (SEQ ID NO: 250) (12) GGTGTCAAACGTGTGGTT, (SEQ ID NO: 251) (13) CCGTGTGCTAGTATTTGT, (SEQ ID NO: 252) (14) TAGTAGAGTTTTGCTTGG, (SEQ ID NO: 253) (15) GATGTAGTAGAGTTTTGC, (SEQ ID NO: 254) (16) TGATGTAGTAGAGTTTTG, (SEQ ID NO: 255) (17) CTGATGTAGTAGAGTTTT, (SEQ ID NO: 256) (19) GCAAGTTGGTTTGTGGTA, (SEQ ID NO: 257) (20) TCTAGGCAATTGTGGTGG, (SEQ ID NO: 258) (21) GTAACTCTGCACTTCCCA, (SEQ ID NO: 259) (22) GTCATCCCTATGTCTTAT, (SEQ ID NO: 260) (23) GTCATATGGTCAGGGTAT, (SEQ ID NO: 261) (24) TGTCATATGGTCAGGGTA, (SEQ ID NO: 262) (25) ATGTCATATGGTCAGGGT, and (SEQ ID NO: 263) (26) TATGTCATATGGTCAGGG.

Methods for reactivating genes on the inactive X chromosome that include administering one or both of a DNA methyltransferase (DNMT) Inhibitor and/or a topoisomerase inhibitor, e.g., etoposide and/or 5′-azacytidine (aza), optionally in combination with an inhibitor of XIST RNA and/or an Xist-interacting protein, e.g., a chromatin-modifying protein, e.g., a small molecule or an inhibitory nucleic acid (such as a small inhibitory RNA (siRNAs) or antisense oligonucleotide (ASO)) that targets XIST RNA and/or a gene encoding an Xist-interacting protein, e.g., a chromatin-modifying protein.

The present disclosure relates to modified extracellular vesicles, e.g., exosomes, comprising an antisense oligonucleotide (ASO), which is capable of reducing and/or inhibiting expression of KRAS mRNA and/or KRAS protein. ASOs that can be used with the modified extracellular vesicles are also disclosed. Also provided herein are methods for using the exosomes and ASOs to treat and/or prevent diseases, such as cancer.

Provided herein are compounds comprising cyclic cell penetrating peptides and antisense compounds. Also provided herein are methods of modulating splicing, inhibiting or regulating translation, mediating degradation, blocking expansions of nucleotide repeats, and treating disease using the aforementioned compounds.

The present disclosure describes compositions of matter comprising a ribonucleoprotein complex comprising a nucleic acid-guided nuclease and a guide RNA, and further comprising and a blocking nucleic acid molecule represented by Formula I, wherein Formula I in the 5′-to-3′ direction comprises: A-(B-L).sub.J-C-M-T-D; wherein A is 0-15 nucleotides in length; B is 4-12 nucleotides in length; L is 3-25 nucleotides in length; J is an integer between 1 and 10; C is 4-15 nucleotides in length; M is 1-25 nucleotides in length or is absent, wherein if M is absent then A-(B-L).sub.J-C and T-D are separate nucleic acid strands; T is 17-135 nucleotides in length and comprises at least 50% sequence complementarity to B and C; D is 0-10 nucleotides in length and comprises at least 50% sequence complementarity to A; and wherein the blocking nucleic acid molecule comprises a sequence complementary to a gRNA.

Disclosed herein are methods for decreasing AlAT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of fibrosis. Disclosed herein are methods for decreasing A1AT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of liver disease, such as, A1ATD associated liver disease, and pulmonary disease, such as, A1ATD associated pulmonary disease in an individual in need thereof. Methods for inhibiting AlAT mRNA and protein expression can also be used as a prophylactic treatment to prevent individuals at risk for developing a liver disease, such as, A1ATD associated liver disease and pulmonary disease, such as, A1ATD associated pulmonary disease.

The present invention relates to a polynucleotide that comprises at least one phosphorothioate internucleoside linkage and at least one guanosine analogue comprising a guanine nucleobase analogue selected from the group consisting of: formula (I) and formula (II). Polynucleotides comprising such guanosine analogues show a relative reduced neurotoxicity compared to polynucleotides with natural guanosine.

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The present embodiments provide methods, compounds, and compositions useful for inhibiting FOXP3 expression, which may be useful for treating, preventing, or ameliorating cancer.

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of FXII RNA in a cell or subject, and in certain instances reducing the amount of FXII protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to prevent, treat, or ameliorate at least one symptom of a thromboembolic condition. Such thromboembolic conditions include deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, and stroke. Such symptoms include pain, shortness of breath, heart burn, cold sweat, fatigue, lightheadedness, dizziness, swelling, cramping, and death. Such compounds, methods, and pharmaceutical compositions are useful to prevent, treat, or ameliorate at least one symptom of hereditary angioedema.