RNAi agents for inhibiting expression of complement component C3 (C3), pharmaceutical compositions thereof, and methods of use
Inventors
Carlson, Jeffrey • Wang, Yichen • Pei, Tao • Hamilton, James C. • MORADI, Hamid
Assignees
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Publication Number
US-12110492-B2
Publication Date
2024-10-08
Expiration Date
Abstract
The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents or siRNAs, able to inhibit Complement Component C3 (C3) gene expression. Also disclosed are pharmaceutical compositions that include C3 RNAi agents and methods of use thereof. The C3 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that comprise N-acetyl-galactosanine, to facilitate the delivery to hepatocyte cells. Delivery of the C3 RNAi agents in vivo provides for inhibition of C3 gene expression. The RNAi agents can be used in methods of treatment of diseases, disorders, or symptoms mediated in part by C3 gene expression, including IgA nephropathy, C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria, and/or other complement-mediated renal diseases.
Core Innovation
The disclosure describes RNAi agents for inhibiting expression of a C3 gene in a human subject. The RNAi agent comprises an antisense strand and a sense strand with defined nucleotide sequences and chemical modifications, including 2′-O-methyl nucleosides, 2′-fluoro nucleosides, phosphorothioate linkages, and an inverted abasic deoxyribose residue (invAb).
A key feature of the disclosed delivery is conjugation of the RNAi agent to an asialoglycoprotein receptor ligand cluster containing N-acetyl-galactosamine (NAG), including (NAG37) and (NAG37)s, to promote hepatocyte-directed in vivo delivery. The sense strand includes a (NAG37)s moiety, and the stated intent is to facilitate hepatocyte uptake and thereby reduce C3 gene expression.
The therapeutic context is treatment of complement-mediated renal diseases, including IgA nephropathy (IgAN) and C3 glomerulopathy (C3G), using pharmaceutical compositions administered in vivo. The disclosure states that administering a therapeutically effective amount of the RNAi agent by subcutaneous injection at a specified dose range inhibits expression of the C3 gene and reduces C3 mRNA/protein-related activity.
Claims Coverage
The provided material presents one independent claim centered on a chemically defined C3-targeting RNAi agent and its subcutaneous administration to treat IgA nephropathy (IgAN) or C3 glomerulopathy (C3G). The claim coverage also includes dependent features concerning formulation, administration frequency, and biological outcome constraints.
C3 gene-inhibiting RNAi for IgAN or C3G treatment
Administering to a human subject a therapeutically effective amount of an RNAi agent for inhibiting expression of a C3 gene, where the RNAi agent comprises an antisense strand and a sense strand.
Chemically defined antisense strand sequence for C3 targeting
Providing an antisense strand comprising the nucleotide sequence (5′→3′) usUfsusCfgAfacaacAfgAfgUfaGfGfgsu (SEQ ID NO:13), with defined modified nucleosides and a phosphorothioate linkage (s).
Chemically defined sense strand with (NAG37)s(invAb) structure
Providing a sense strand comprising the nucleotide sequence (5′→3′) (NAG37)s(invAb)sacccuacuCfUfGfuuguucgaaas(invAb) (SEQ ID NO:14), where a is 2′-O-methyl adenosine; c is 2′-O-methyl cytidine; g is 2′-O-methyl guanosine; u is 2′-O-methyl uridine; Af is 2′-fluoro adenosine; Cf is 2′-fluoro cytidine; Gf is 2′-fluoro guanosine; Uf is 2′-fluoro adenosine; s is a phosphorothioate linkage; and (invAb) is an inverted abasic deoxyribose residue.
Subcutaneous administration within a defined dose range
Administering the RNAi agent by subcutaneous injection at a dose of between about 25 mg and about 400 mg of RNAi agent.
Therapeutic RNAi formulation in an aqueous sodium phosphate buffer
Formulating the RNAi agent at 200 mg/mL in an aqueous sodium phosphate buffer containing about 0.5 mM sodium phosphate monobasic and 0.5 mM sodium phosphate dibasic.
Administration frequency of the subcutaneous RNAi treatment
Administering the RNAi agent to the human subject no more frequently than once every twelve weeks.
Serum C3 protein decrease as a treatment outcome
Performing the method such that the subject’s serum C3 protein level is decreased.
Reduction of alternative complement pathway hemolytic activity
Reducing the subject’s alternative complement pathway hemolytic activity (AH50) by at least about 50%, or approximately 90% or more.
The claim set centers on subcutaneous administration of a defined C3-targeting RNAi agent to treat IgAN or C3G, with dose and frequency constraints and biological outcome requirements including decreased serum C3 protein and reduced AH50.
Stated Advantages
Inhibits expression of a C3 gene.
Decreases serum C3 protein level.
Reduces alternative complement pathway hemolytic activity (AH50).
Documented Applications
Treatment of IgA nephropathy (IgAN) or C3 glomerulopathy (C3G) in a human subject in need thereof by administering a therapeutically effective amount of a C3 gene-inhibiting RNAi agent.
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