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US 2020/0263183 A1Published application
COMPLEMENT COMPONENT iRNA COMPOSITIONS AND METHODS OF USE THEREOF
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsAnna Borodovsky, Brian Bettencourt
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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.
Claims28
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, herein 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, wherein said sense strand comprising a region of complementarity which comprises at least 15 continuous 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.
8 more elements
3-5. (canceled)
7-8. (canceled)
13-32. (canceled)
A double stranded RNAi agent for inhibiting expression of complement factor B (CFB) in a cell,
- wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region,
- wherein said sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence of any one of SEQ ID NOs:1-5, 27, and 30, and said antisense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence of any one of SEQ ID NOs:12-16, 33, and 36,
- wherein substantially all of the nucleotides of said sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus,
- wherein substantially all of the nucleotides of said antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and
- wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.
4 more elements
A double stranded RNAi agent for inhibiting expression of complement component C3 in a cell,
- wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region,
- wherein said sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence of any one of SEQ ID NOs:6-8, 28, and 31, and said antisense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence of any one of SEQ ID NOs:17-19, 34, and 37,
- wherein substantially all of the nucleotides of said sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus,
- wherein substantially all of the nucleotides of said antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and
- wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.
4 more elements
A double stranded RNAi agent for inhibiting expression of complement component C9 in a cell,
- wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region,
- wherein said sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence of any one of SEQ ID NOs:9-11, 29, and 32, and said antisense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence of any one of SEQ ID NOs:20-22, 35, and 38,
- wherein substantially all of the nucleotides of said sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus,
- wherein substantially all of the nucleotides of said antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and
- wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.
4 more elements
Dependencies are inferred from the claim text.