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.

1 - 3 . (canceled) 
     
     
         4 . The dsRNA agent of  claim 21 , wherein each strand is independently 17-25 nucleotides in length. 
     
     
         5 . The dsRNA agent of  claim 21 , wherein each strand is independently 17-23 nucleotides in length. 
     
     
         6 . The dsRNA agent of  claim 21 , wherein each strand is independently 17-21 nucleotides in length. 
     
     
         7 . The dsRNA agent of  claim 21 , 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 21 , 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 21 , 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 21 , 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 21 , 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 21 , wherein the ligand comprises an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         13 . The dsRNA agent of  claim 21 , 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 . (canceled) 
     
     
         15 . The dsRNA agent of  claim 21 , 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 . (canceled) 
     
     
         19 . An isolated cell containing the dsRNA agent of  claim 21 . 
     
     
         20 . A pharmaceutical composition for inhibiting expression of a complement component C3 gene, comprising the dsRNA agent of  claim 21 . 
     
     
         21 . A double stranded ribonucleic acid (dsRNA) agent selected from the group consisting of;
 (a) a dsRNA agent for inhibiting expression of complement factor B (CFB) in a cell, wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides from any one of the nucleotide sequence of SEQ ID NOs:1-5, 27, and 30, and said antisense strand comprises at least 15 contiguous nucleotides from any one of the nucleotide sequence of SEQ ID NOs:12-16, 33, and 36;   (b) a dsRNA agent for inhibiting expression of complement factor B (CFB) in a cell, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides from any one of the antisense sequences listed in Table 3 and 4;   (c) a dsRNA agent for inhibiting expression of complement component C3 in a cell, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides from any one of the antisense sequences listed in Table 5 and 6;   (d) a dsRNA agent for inhibiting expression of complement component C3 in a cell, wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides from any one of the nucleotide sequence of SEQ ID NOs:6-8, 28, and 31, and said antisense strand comprises at least 15 contiguous nucleotides from any one of the nucleotide sequence of SEQ ID NOs:17-19, 34, and 37;   (e) a dsRNA agent for inhibiting expression of complement component C9 in a cell, wherein said dsRNA comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides from any one of the nucleotide sequence of SEQ ID NOs:9-11, 29, and 32, and said antisense strand comprises at least 15 contiguous nucleotides from any one of the nucleotide sequence of SEQ ID NOs:20-22, 35, and 38; and   (f) a dsRNA agent for inhibiting expression of complement component C9 in a cell, wherein said dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides from any one of the antisense sequences listed in Table 7 and 8;   wherein the sense strand and the antisense strand form a double stranded region,   wherein the dsRNA agent comprises at least one modified nucleotide, and   a ligand.   
     
     
         22 . A method of inhibiting complement factor B (CFB) expression in a cell, the method comprising:
 (a) contacting the cell with the agent of  claim 21 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a CFB gene, thereby inhibiting expression of the CFB gene in the cell.   
     
     
         23 . A method of inhibiting complement component 3 (C3) expression in a cell, the method comprising:
 (a) contacting the cell with the agent of  claim 21 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a C3 gene, thereby inhibiting expression of the C3 gene in the cell.   
     
     
         24 . A method of inhibiting complement component 9 (C9) expression in a cell, the method comprising:
 (a) contacting the cell with the agent of  claim 21 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a C9 gene, thereby inhibiting expression of the C9 gene in the cell.