Complement component C3 iRNA compositions and methods of use thereof
Inventors
Keating, Mark • McIninch, James D. • Fishilevich, Elane • Yucius, Kristina • Solomon, Sarah • Schlegel, Mark K. • Castoreno, Adam • Kaittanis, Charalambos
Assignees
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Publication Number
US-12258565-B2
Publication Date
2025-03-25
Expiration Date
Abstract
The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the complement component C3 gene (C3). The invention also relates to methods of using such RNAi agents to inhibit expression of a C3 gene and to methods of preventing and treating a C3-associated disorder, e.g., cold agglutinin disease (CAD), warm autoimmune hemolytic anemia, and paroxysmal nocturnal hemoglobinuria (PNH), lupis nephritis (LN), bullous pemphigoid, pemphigus, e.g., pemphigus vulgaris (PV) and pemphigus foliaceus (PF), and C3 glomerulopathy.
Core Innovation
A double stranded ribonucleic acid (dsRNA) agent is provided for inhibiting expression of complement component C3 in a cell, or a pharmaceutically acceptable salt thereof. The dsRNA agent comprises a sense strand and an antisense strand defined by specific nucleotide sequences associated with SEQ ID NO:4188 and SEQ ID NO:4367, with limited differences from those sequences or exact sequence composition in additional embodiments. The strands incorporate defined chemical modifications, including 2′-O-methyl (2′-OMe) A, G, C, and U, 2′-fluoro A, G, C, and U, and a phosphorothioate linkage.
In an embodiment, the 3′-end of the sense strand of the dsRNA agent, or a pharmaceutically acceptable salt thereof, is conjugated to a ligand as shown in a schematic, where X is O. The specification also discusses carbohydrate conjugates, including GalNAc/GalNAc derivative conjugates, and linker types described as monovalent, bivalent, and trivalent linkers, including cleavable and non-cleavable linkers. These definitions combine sequence constraints, chemical modification definitions, and ligand conjugation at the sense strand 3′-end.
Claims Coverage
The independent claims cover three core subject matters: a C3-inhibiting dsRNA defined by strand similarity limits to specified SEQ ID sequences with defined nucleotide chemistry, the same general dsRNA concept further requiring 3′-end ligand conjugation, and a dsRNA defined with exact sense/antisense sequences with defined nucleotide chemistry and 3′-end ligand conjugation. Across the independent claims, the total inventive features are sequence-definition with mismatch/consisting limits, specified 2′-O-methyl and 2′-fluoro nucleotide identities, phosphorothioate linkage, and ligand conjugation at the sense strand 3′-end.
Complement component C3 inhibiting dsRNA with limited base differences from SEQ ID strands
A dsRNA agent for inhibiting expression of complement component C3 in a cell (or a pharmaceutically acceptable salt thereof) comprising a sense strand differing by no more than 4 bases from the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand differing by no more than 4 bases from the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
Defined 2′-O-methyl, 2′-fluoro, and phosphorothioate nucleotides
In the dsRNA agent, where a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf, and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage.
Sense strand 3′-end ligand conjugation with X is O
The 3′-end of the sense strand of the dsRNA agent (or a pharmaceutically acceptable salt thereof) is conjugated to a ligand as shown in the schematic, wherein X is O.
Complement component C3 inhibiting dsRNA with exact sense/antisense sequences
A dsRNA agent for inhibiting expression of complement component C3 in a cell (or a pharmaceutically acceptable salt thereof) consisting of a sense strand consisting of the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand consisting of the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
Across the independent claims, the dsRNA agent is defined by strand sequence constraints relative to SEQ ID NO:4188 and SEQ ID NO:4367, defined nucleoside modifications and phosphorothioate linkage, and ligand conjugation at the sense strand 3′-end as shown in a schematic with X = O.
Stated Advantages
Inhibits expression of complement component C3 in a cell.
Provides a dsRNA agent with specific chemical nucleotide modifications including 2′-O-methyl and 2′-fluoro nucleotides and phosphorothioate linkage.
Conjugates the 3′-end of the sense strand to a ligand.
Treat complement component C3-associated diseases by C3 gene-expression inhibition.
Documented Applications
In vitro free-uptake and transfection single-dose screens in primary cynomolgus hepatocytes measuring % remaining C3 mRNA.
In vivo screening in mice using an AAV8 vector expressing human C3 mRNA fragment with reductions in human C3 mRNA.
Non-human primate dosing studies in Cynomolgus monkeys with monitoring of C3 protein levels by ELISA and functional alternative-pathway activity (CAP assay).
Inhibiting expression of complement component C3 in a cell.
Use as an isolated cell containing the dsRNA agent and/or pharmaceutically acceptable salt thereof in embodiments of claims depending from the independent claims.
Use as a pharmaceutical composition comprising the dsRNA agent and/or pharmaceutically acceptable salt thereof in embodiments of claims depending from the independent claims.
Treatment and prevention of C3-associated disorders including cold agglutinin disease (CAD), warm autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria (PNH), lupus nephritis (LN), bullous pemphigoid, pemphigus vulgaris (PV), pemphigus foliaceus (PF), and C3 glomerulopathy.
Treatment of warm autoimmune hemolytic anemia by C3 gene-expression inhibition.
Treatment of paroxysmal nocturnal hemoglobinuria (PNH) by C3 gene-expression inhibition.
Treatment of lupus nephritis (LN) by C3 gene-expression inhibition.
Treatment of bullous pemphigoid by C3 gene-expression inhibition.
Treatment of pemphigus (PV/PF) by C3 gene-expression inhibition.
Treatment of C3 glomerulopathy by C3 gene-expression inhibition.
In vitro single-dose screening data for C3-targeting dsRNA duplexes in Hep3B and PMH cells with reported dose levels and duplex designs.
In vivo mouse evaluation using AAV8 vectors encoding human complement component C3 portions, with liver mRNA RT-qPCR analysis normalized to PBS vehicle and percent changes reported for human complement component C3 mRNA.
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