Organic compositions to treat EPAS1-related diseases

1. A composition comprising an RNAi agent for inhibiting expression of an EPAS1(Hif2 alpha) gene, wherein the RNAi agent comprises a sense strand and an antisense strand, wherein the antisense strand comprises the sequence of 5′-UCAUGAAAUCGUUACGUUG-3′ (SEQ ID NO: 70), and the sense strand comprises the sequence of 5′-CAACGUAACGAUUUCAUGA-3′ (SEQ ID NO: 51), and wherein the RNAi agent comprises at least one sugar backbone modification or at least one 2′-modified nucleotide.

2. The composition of claim 1 , wherein the composition further comprises a second RNAi agent that inhibits the EPAS1 (Hif2 alpha) gene.

3. The composition of claim 1 , wherein the antisense strand is about 30 or fewer nucleotides in length.

4. The composition of claim 1 , wherein the sense strand and the antisense strand form a duplex region about 15 to about 30 nucleotide pairs in length.

5. The composition of claim 1 , wherein the antisense strand and the sense strand are both about 19 to about 23 nucleotides in length.

6. The composition of claim 1 , wherein the RNAi agent comprises a 2′-modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOPE), and 2′-O-N-methylacetamido (2′-O-NMA).

7. The composition of claim 1 , wherein the RNAi agent comprises a blunt end.

8. The composition of claim 1 , wherein the RNAi agent comprises an overhang having 1 to 4 unpaired nucleotides.

9. The composition of claim 1 , wherein the RNAi agent is ligated to one or more diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.

10. The composition of claim 1 , wherein the antisense strand is: U pC pA pU004 pG pA pA pA pU004 pC004 pG pU004 pU004 pA pC004 pG pU004 pU004 pG pU004 pU004 (SEQ ID NO: 138), and wherein the sense strand is: C pA pA pC pG pU004 pA pA pC pG pA pU004 pU004 pU004 pC pA pU004 pG pA pU004 pU004 (SEQ ID NO: 157), wherein p is a phosphate linkage, U is uridine, C is cytidine, A is adenosine, G is guanosine, U004 is 2′-O-methyl uridine modified nucleotide, and C004 is 2′-O-methyl cytosine modified nucleotide.

11. The composition of claim 1 , wherein the antisense strand is: U pC pA pU004pG pA pA pA pU004 pC pG pU004 pU004 pA pC pG pU004 pU004 pG pU004 pU004 (SEQ ID NO: 108), and the sense strand is: C004 pA pA pC004 pG pU004 pA pA pC004 pG pA pU004 pU004 pU004 pC004 pA pU004 pG pA pU004 pU004 (SEQ ID NO: 89), wherein p is a phosphate linkage, U is uridine, C is cytidine, A is adenosine, G is guanosine, U004 is 2′-O-methyl uridine modified nucleotide, and C004 is 2′-O-methyl cytosine modified nucleotide.

12. The composition of claim 1 , wherein the antisense strand is: U pC pA pU004 pG pA pA pA pU004 pC004 pG pU004 pU004 pA pC004 pG pU004 pU004 pG pU004 pU004(SEQ ID NO: 193), and the sense strand is: C pA pA pC pG pU004 pA pA pC pG pA pU004pU004 pU004 pC pA pU004 pG pA pU004 pU004 (SEQ ID NO: 175), wherein p is a phosphate linkage, U is uridine, C is cytidine, A is adenosine, G is guanosine, U004 is 2′-O-methyl uridine modified nucleotide, and C004 is 2′-O-methyl cytosine modified nucleotide.

13. A method of inhibiting the expression of an EPAS 1 (Hif2 alpha) gene in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1 .

14. The method of claim 13 , wherein the individual is afflicted with or susceptible to an EPAS 1-related disease.

15. The method of claim 14 , wherein the EPAS1-related disease is cancer, metastases, astrocytoma, bladder cancer, breast cancer, chondrosarcoma, colorectal carcinoma, gastric carcinoma, glioblastoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, neuroblastoma, non-small cell lung cancer, melanoma, multiple myeloma, ovarian cancer, rectal cancer, renal cancer, clear cell renal cell carcinoma (and metastases of this and other cancers), gingivitis, psoriasis, Kaposi's sarcoma-associated herpesvirus, preeclampsia, inflammation, chronic inflammation, neovascular diseases, or rheumatoid arthritis.

16. The method of claim 14 , wherein the EPAS1-related disease is cancer.

17. The method of claim 13 , wherein the method further comprises administering an additional disease treatment.

18. The method of claim 13 , wherein the composition further comprises a second RNAi agent to EPAS1 (Hif2 alpha).

19. A method of treating a subject afflicted with or susceptible to an EPAS1-related disease, or preventing, modulating, or ameliorating in a subject a pathological state mediated at least in part by EPAS1 (Hif2 alpha) gene expression, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1 .

20. The method of claim 19 , wherein the EPAS1-related disease is cancer, metastases, astrocytoma, bladder cancer, breast cancer, chondrosarcoma, colorectal carcinoma, gastric carcinoma, glioblastoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, neuroblastoma, non-small cell lung cancer, melanoma, multiple myeloma, ovarian cancer, rectal cancer, renal cancer, clear cell renal cell carcinoma (and metastases of this and other cancers), gingivitis, psoriasis, Kaposi's sarcoma-associated herpesvirus, preeclampsia, inflammation, chronic inflammation, neovascular diseases, or rheumatoid arthritis.