Compositions and methods for inhibition of expression of protein C (PROC) genes
View Patent ↗The invention relates to double-stranded ribonucleic acid (dsRNA) targeting a PROC gene, and methods of using the dsRNA to inhibit expression of PROC.
1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of a Protein C (PROC) gene, wherein the dsRNA comprises a sense strand and an antisense strand each 30 nucleotides or less in length, wherein the antisense strand is complementary to at least 15 contiguous nucleotides of nucleotides SEQ ID NO:159.
2. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of gene, wherein the dsRNA comprises a sense strand and an antisense strand wherein the sense strand consists of the nucleotide sequence of the sense strand of AD-48898.1UM (SEQ ID NO:159) and the antisense strand consists of the nucleotide sequence of the antisense strand of AD-48898.1UM (SEQ ID NO:213).
3. The dsRNA of claim 1 , wherein the antisense strand comprises the antisense strand of AD-48898.1UM (SEQ ID NO:213).
4. The dsRNA of claim 1 , wherein at least one nucleotide of the dsRNA is a modified nucleotide.
5. The dsRNA of claim 4 , wherein the modified nucleotide is chosen from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group.
6. The dsRNA of claim 4 , wherein the modified nucleotide is chosen from the group consisting of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.
7. The dsRNA of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
8. The dsRNA of claim 1 , wherein each strand comprises a 3′ overhang of at 2 nucleotides.
9. The dsRNA of claim 1 , further comprising a ligand.
10. The dsRNA of claim 9 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.
11. The dsRNA of claim 1 , further comprising at least one N-Acetyl-Galactosamine.
12. A cell comprising the dsRNA of claim 1 .
13. A vector encoding at least one strand of the dsRNA of claim 1 .
14. A cell comprising the vector of claim 13 .
15. A pharmaceutical composition for inhibiting expression of an PROC gene comprising the dsRNA of claim 1 .
16. The pharmaceutical composition of claim 15 , comprising a lipid formulation.
17. The pharmaceutical composition of claim 15 , comprising a lipid formulation comprising (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3).
18. A method of inhibiting PROC expression in a cell, the method comprising:
(a) contacting 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 an PROC gene, thereby inhibiting expression of the PROC gene in the cell.
19. The method of claim 18 , wherein the PROC expression is inhibited by at least 30%.
20. A method of treating a disorder mediated by PROC expression comprising administering to a human in need of such treatment a therapeutically effective amount of the PROC dsRNA of claim 1 .
21. The method of claim 20 , wherein the disorder is a bleeding disorder.
22. The method of claim 20 , wherein the disorder is hemophilia.
23. The method of claim 20 , wherein administration causes an increase in blood clotting and/or a decrease in PROC protein accumulation.
24. The method of claim 20 , wherein the dsRNA or the pharmaceutical composition is administered at a dose of about 0.01 mg/kg to about 10 mg/kg or about 0.5 mg/kg to about 50 mg/kg.
25. A pharmaceutical composition for inhibiting expression of an PROC gene comprising the dsRNA of claim 2 .
26. The pharmaceutical composition of claim 25 , comprising a lipid formulation.
27. The pharmaceutical composition of claim 25 , comprising a lipid formulation comprising (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3).
28. A method of inhibiting PROC expression in a cell, the method comprising:
(a) contacting 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 an PROC gene, thereby inhibiting expression of the PROC gene in the cell.
29. A method of treating a disorder mediated by PROC expression comprising administering to a human in need of such treatment a therapeutically effective amount of the PROC dsRNA of claim 2 .
30. The method of claim 29 , wherein the disorder is a bleeding disorder.
31. The method of claim 29 , wherein the disorder is hemophilia.
32. The method of claim 29 , wherein administration causes an increase in blood clotting and/or a decrease in PROC protein accumulation.
33. The method of claim 29 , wherein the dsRNA or the pharmaceutical composition is administered at a dose of about 0.01 mg/kg to about 10 mg/kg or about 0.5 mg/kg to about 50 mg/kg.