GNAQ targeted dsRNA compositions and methods for inhibiting expression

1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of a G-alpha q subunit (GNAQ) of a heterotrimeric G gene, comprising a sense strand consisting SEQ ID: 167 and an antisense strand consisting of SEQ ID NO:168.

2. The dsRNA of claim 1 , wherein the sense strand consists of SEQ ID NO:1565 (AGuAcAAucuGGucuAAuudTdT) and the antisense strand consists of SEQ ID NO:1566 (AAUuAGACcAGAUUGuACUdTdT) wherein each strand includes 2′-O-methyl ribonucleotides as indicated by a lower case letter “c” and “u”.

3. The dsRNA of claim 1 , wherein NN of each strand comprises a 3′ overhang consisting of dTdT.

4. The dsRNA of claim 1 , comprising a modification that causes the dsRNA to have increased stability in a biological sample.

5. The dsRNA of claim 1 , comprising at least one modified nucleotide.

6. The dsRNA of claim 5 , wherein said modified nucleotide is selected from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified, nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.

7. The dsRNA of claim 5 , comprising at least one 2′-O-methyl modified nucleotide and at least one 2′-deoxythymidine-3′-phosphate nucleotide comprising a 5′-phosphorothioate group.

8. The dsRNA of claim 1 , further comprising a ligand.

9. The dsRNA of claim 8 , wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA.

10. A composition for inhibiting expression of a GNAQ gene comprising the dsRNA of claim 1 and pharmaceutical formulation.

11. The composition of claim 10 wherein the pharmaceutical formulation is a lipid formulation.

12. The composition of claim 10 , wherein the pharmaceutical formulation is a (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3) comprising formulation.

13. An isolated cell containing the dsRNA of claim 1 .

14. A vector comprising a nucleotide sequence that encodes at least one strand of the dsRNA of claim 1 .

15. An isolated cell comprising the vector of claim 14 .

16. The dsRNA of claim 1 , wherein said dsRNA, upon contact with a cell expressing said GNAQ, inhibits expression of said GNAQ gene by at least 40% compared to a cell not so contacted.

17. The dsRNA of claim 1 , wherein the dsRNA has an IC50 of less than 10 pM.

18. The dsRNA of claim 1 , wherein administration of 0.1 nM of the dsRNA to a A375 cell results in about 66% inhibition of GNAQ mRNA expression as measured by a real time PCR assay or administration of 1 nM of the dsRNA to a A375 cell results in about 61% inhibition of GNAQ mRNA expression as measured by a real time PCR assay or administration of 1 nM of the dsRNA to an A579 cell results in about 82% inhibition of GNAQ tnRNA expression as measured by a real time PCR assay or administration of 10 nM of the dsRNA to a OMM1.3 cell results in about 42% inhibition of GNAQ mRNA expression as measured by a real time PCR assay or administration of the dsRNA to a UMEL202 cell results in about 81% inhibition of GNAQ mRNA expression as measured by a real time PCR assay.

19. A method of inhibiting GNAQ expression in a cell, the method comprising:

(a) introducing into the cell the dsRNA of claim 1 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a GNAQ gene, thereby inhibiting expression of the GNAQ gene in the cell.

20. A method of treating a disorder mediated by GNAQ expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of claim 1 .

21. The method of claim 20 , wherein the human has uveal melanoma, cutaneous melanoma, Blue nevi, Nevi of Ota, a small lung tumor, or a neuroendocrine tumors.

22. The dsRNA of claim 2 , further comprising a ligand.

23. The dsRNA of claim 2 , further comprising a ligand conjugated to the 3 ′-end of the sense strand of the dsRNA.

24. A composition for inhibiting expression of a GNAQ gene comprising the dsRNA of claim 2 and pharmaceutical formulation.

25. The composition of claim 24 , wherein the pharmaceutical formulation is a lipid formulation.

26. An isolated cell containing the dsRNA of claim 2 .

27. A method of inhibiting GNAQ expression in a cell, the method comprising:

(a) introducing into the cell the dsRNA of claim 2 and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a GNAQ gene, thereby inhibiting expression of the GNAQ gene in the cell.

28. A method of treating a disorder mediated by GNAQ expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of claim 2 .

29. The method of claim 28 , wherein the human has uveal melanoma, cutaneous melanoma, Blue nevi, Nevi of Ota, a small lung tumor, or a neuroendocrine tumors.