Compositions and Methods for Inhibition of Expression of Apolipoprotein C-III (APOC3) Genes

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) targeting an APOC3 gene, and methods of using the dsRNA to inhibit expression of APOC3.

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of an APOC3 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 . (canceled) 
     
     
         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 , 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 APOC3 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 MC3. 
     
     
         18 . A method of inhibiting APOC3 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 APOC3 gene, thereby inhibiting expression of the APOC3 gene in the cell.   
     
     
         19 . The method of  claim 18 , wherein the APOC3 expression is inhibited by at least 30%. 
     
     
         20 . A method of treating a disorder mediated by APOC3 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the APOC3 dsRNA of  claim 1 . 
     
     
         21 .- 24 . (canceled)