Compositions and methods for inhibition of expression of protein c (proc) genes

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) targeting a PROC gene, and methods of using the dsRNA to inhibit expression of PROC.

We claim: 
     
         1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of an PROC gene, wherein the dsRNA comprises a sense strand and an antisense strand each 30 nucleotides or less in length, wherein the antisense strand comprises at least 15 contiguous nucleotides of an antisense sequence in Table 1, 2, 6, 7, or 10. 
     
     
         2 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of an PROC gene, wherein the dsRNA consists of AD-48953 or AD-46165 or AD-48988 or AD-48788. 
     
     
         3 . The dsRNA of  claim 1 , wherein the sense strand sequence is selected from Table 1, 2, 6, 7, or 10, and the antisense strand is selected from Table 1, 2, 6, 7, or 10. 
     
     
         4 . The dsRNA of  claim 1  or  2 , 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 any of the above claims, wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide. 
     
     
         8 . The dsRNA of  claim 1  or  2 , wherein each strand comprises a 3′ overhang of at 2 nucleotides. 
     
     
         9 . The dsRNA of any of the above claims, 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 any of the above claims, further comprising at least one N-Acetyl-Galactosamine. 
     
     
         12 . A cell comprising the dsRNA of any of the above claims. 
     
     
         13 . A vector encoding at least one strand of the dsRNA of any of the above claims. 
     
     
         14 . A cell comprising the vector of  claim 13 . 
     
     
         15 . A pharmaceutical composition for inhibiting expression of an PROC gene comprising the dsRNA of any of the above claims. 
     
     
         16 . The pharmaceutical composition of  claim 15 , comprising a lipid formulation. 
     
     
         17 . The pharmaceutical composition of  claim 15 , comprising a lipid formulation comprising MC3. 
     
     
         18 . A method of inhibiting PROC expression in a cell, the method comprising:
 (a) contacting the cell the dsRNA of any of the above claims; 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  or  2  or  11  or the pharmaceutical composition of  claim 15 ,  16 , or  17 . 
     
     
         21 . The method of  claim 20 , wherein the disorder is a bleeding disorder. 
     
     
         22 . The method of  claim 20 , wherein the disorder is hemophelia. 
     
     
         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.