COMPLEMENT COMPONENT iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the complement factor B (CFB) gene, the complement component C3 gene, and the complement component C9 gene and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of CFB, C9 and/or C3 and to treat subjects having a complement component-associated disease, e.g., paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

We claim: 
     
         1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3 in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
 wherein the sense strand comprises at least 15 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 3301-3325 of SEQ ID NO:6,   wherein each strand is independently 15-25 nucleotides in length,   wherein at least one nucleotide is a modified nucleotide, and   wherein at least one strand is conjugated to a ligand.   
     
     
         2 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3 in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
 wherein the sense strand comprises at least 15 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 3301-3325 of SEQ ID NO:6,   wherein each strand is independently 15-25 nucleotides in length,   wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, and   wherein at least one strand is conjugated to a ligand.   
     
     
         3 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3 in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
 wherein the sense strand comprises at least 15 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 3301-3325 of SEQ ID NO:6,   wherein each strand is independently 15-25 nucleotides in length,   wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides, and   wherein at least one strand is conjugated to a ligand.   
     
     
         4 . The dsRNA agent of  claim 1 , wherein each strand is independently 17-25 nucleotides in length. 
     
     
         5 . The dsRNA agent of  claim 1 , wherein each strand is independently 17-23 nucleotides in length. 
     
     
         6 . The dsRNA agent of  claim 1 , wherein each strand is independently 17-21 nucleotides in length. 
     
     
         7 . The dsRNA agent of  claim 1 , wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides. 
     
     
         8 . The dsRNA agent of  claim 1 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides. 
     
     
         9 . The dsRNA agent of  claim 1 , wherein the at least one modified nucleotides has a nucleotide modification selected from the group consisting of an LNA, a CRN, a cET, aUNA, an HNA, a CeNA, a 2′-methoxyethyl, a 2′-O-methyl, a 2′-O-alkyl, a 2′-O-allyl, a 2′-C-allyl, a 2′-fluoro, a 2′-deoxy, a 2′-hydroxyl modification, and combinations thereof. 
     
     
         10 . The dsRNA agent of  claim 1 , wherein the at least one modified nucleotide is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, an abasic nucleotide, and a 2′-amino modified nucleotide. 
     
     
         11 . The dsRNA agent of  claim 1 , wherein the at least one modified nucleotide is a 2′-O-methyl modified nucleotide or a 2′-fluoro modified nucleotide. 
     
     
         12 . The dsRNA agent of  claim 1 , wherein the ligand comprises an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         13 . The dsRNA agent of  claim 1 , wherein at least one of the 5′-end or the 3′-end of the sense strand of the dsRNA agent is a blunt end. 
     
     
         14 . The dsRNA agent of  claim 1 , wherein both the 5′-end and the 3′-end of the sense strand of the dsRNA agent are a blunt end. 
     
     
         15 . The dsRNA agent of  claim 1 , wherein the dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage. 
     
     
         16 . The dsRNA agent of  claim 15 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand. 
     
     
         17 . The dsRNA agent of  claim 16 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at both the 5′- and 3′-terminus of one strand. 
     
     
         18 . The dsRNA agent of  claim 17 , wherein the strand is the antisense strand. 
     
     
         19 . A cell containing the dsRNA agent of  claim 1 . 
     
     
         20 . A pharmaceutical composition for inhibiting expression of a complement component C3 gene, comprising the dsRNA agent of  claim 1 .