COMPOSITIONS AND METHODS FOR INHIBITION OF EXPRESSION OF APOLIPOPROTEIN C-III (APOC3) GENES
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 forming a double stranded region, wherein the sense strand and the antisense strand are each 30 nucleotides or less in length, and wherein the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of any one of the antisense strand nucleotide sequences in any one of Tables 1, 2, 6, 7, or 10.
2 . (canceled)
3 . The dsRNA of claim 1 , wherein the nucleotide sequence of the sense strand is selected from any one of the sense strand nucleotide sequences in any one of Tables 1, 2, 6, 7, or 10, and the nucleotide sequence of the antisense strand is selected from any one of the antisense strand nucleotide sequences in any one of Tables 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 selected 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 selected 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 9 wherein the ligand is an N-Acetyl-Galactosamine derivative.
12 . An isolated cell comprising the dsRNA of claim 1 .
13 . A vector encoding at least one strand of the dsRNA of claim 1 .
14 . An isolated 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 with 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)