APOLIPOPROTEIN C3 (APOC3) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the apolipoprotein C3 (APOC3) gene, and methods of using such RNAi agents to inhibit expression of APOC3 and methods of treating subjects having an APOC3 associated disorder, e.g., hypertriglyceridemia.

We claim: 
     
         1 . A double stranded RNAi agent for inhibiting expression of apolipoprotein C3 (APOC3) in a cell, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence of 5′-AAGGGACAGUAUUCUCAGUGC-3′ (SEQ ID NO:125), and wherein the antisense strand comprises at least 18 contiguous nucleotides from the nucleotide sequence of 5′-GCACUGAGAAUACUGUCCCUUUU-3′ (SEQ ID NO:228), wherein
 all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides; 
 the sense strand is conjugated to a ligand; 
 the sense strand comprises at least one phosphorothioate internucleotide linkage at the 3′terminus and at least one phosphorothioate internucleotide linkage at the 5′ terminus; and 
 the antisense strand comprises at least one phosphorothioate internucleotide linkage at the 3′terminus and at least one phosphorothioate internucleotide linkage at the 5′ terminus. 
 
     
     
         2 . The double stranded RNAi agent of  claim 1 , wherein the modified nucleotides are selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, and an abasic nucleotide. 
     
     
         3 . The double stranded RNAi agent of  claim 1 , wherein the sense strand contains at least one motif of three 2′-flouro modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′ end. 
     
     
         4 . The double stranded RNAi agent of  claim 1 , wherein the sense strand comprises at least one abasic nucleotide. 
     
     
         5 . The double stranded RNAi agent of  claim 1 , wherein the double stranded region comprises a non-canonical base pair. 
     
     
         6 . The double stranded RNAi agent of  claim 1 , wherein each strand is 17-30 nucleotides in length. 
     
     
         7 . The double stranded RNAi agent of  claim 1 , wherein the RNAi agent is a double ended bluntmer of 21 nucleotides in length. 
     
     
         8 . The double stranded RNAi agent of  claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     
     
         9 . A pharmaceutical composition comprising the double stranded double stranded RNAi agent of  claim 1 . 
     
     
         10 . A double stranded RNAi agent for inhibiting expression of apolipoprotein C3 (APOC3) in a cell, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence of 5′-AAGGGACAGUAUUCUCAGUGC-3′ (SEQ ID NO:125), and wherein the antisense strand comprises at least 18 contiguous nucleotides from the nucleotide sequence of 5′-GCACUGAGAAUACUGUCCCUUUU-3′ (SEQ ID NO:228), wherein
 all of the nucleotides of the sense strand and all of the nucleotide of the antisense strand are modified nucleotides selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, and an abasic nucleotide, 
 the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker, 
 the sense strand comprises at least one phosphorothioate internucleotide linkage at the 3′terminus and at least one phosphorothioate internucleotide linkage at the 5′ terminus, 
 the antisense strand comprises at least one phosphorothioate internucleotide linkage at the 3′terminus and at least one phosphorothioate internucleotide linkage at the 5′ terminus, and 
 the sense strand comprises at least one abasic nucleotide. 
 
     
     
         11 . The double stranded RNAi agent of  claim 10 , wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′ end, and. 
     
     
         12 . The double stranded RNAi agent of  claim 10 , wherein the double stranded region comprises a non-canonical base pair. 
     
     
         13 . The double stranded RNAi agent of  claim 10 , wherein each strand is 17-30 nucleotides in length. 
     
     
         14 . The double stranded RNAi agent of  claim 10 , wherein the RNAi agent is a double ended bluntmer of 21 nucleotides in length. 
     
     
         15 . A pharmaceutical composition comprising the double stranded RNAi agent of  claim 10 . 
     
     
         16 . A double stranded RNAi agent for inhibiting expression of apolipoprotein C3 (APOC3) in a cell, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence of 5′-AAGGGACAGUAUUCUCAGUGC-3′ (SEQ ID NO:125), and wherein the antisense strand comprises at least 18 contiguous nucleotides from the nucleotide sequence of 5′-GCACUGAGAAUACUGUCCCUUUU-3′ (SEQ ID NO:228), wherein
 all of the nucleotides of the sense strand and all of the nucleotide of the antisense strand are modified nucleotides selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, and an abasic nucleotide, 
 the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker, 
 the sense strand comprises at least one phosphorothioate internucleotide linkage at the 3′terminus and at least one phosphorothioate internucleotide linkage at the 5′ terminus, 
 the antisense strand comprises at least one phosphorothioate internucleotide linkage at the 3′terminus and at least one phosphorothioate internucleotide linkage at the 5′ terminus, 
 the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′ end, and 
 the sense strand comprises at least one abasic nucleotide. 
 
     
     
         17 . The double stranded RNAi agent of  claim 16 , wherein the double stranded region comprises a non-canonical base pair. 
     
     
         18 . The double stranded RNAi agent of  claim 16 , wherein each strand is 17-30 nucleotides in length. 
     
     
         19 . The double stranded RNAi agent of  claim 16 , wherein the RNAi agent is a double ended bluntmer of 21 nucleotides in length. 
     
     
         20 . A pharmaceutical composition comprising the double stranded RNAi agent of  claim 16 .