Small interfering RNA targeting CFB and uses thereof
Inventors
Geng, Xin • ZHANG, Chunyang • Wang, Shiyu • Wang, Weimin
Assignees
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Publication Number
US-12735709-B2
Publication Date
2026-09-15
Expiration Date
Abstract
This disclosure relates to isolated oligonucleotides comprising duplex regions targeting human CFB mRNA, and delivery systems, and compositions comprising the same, and methods of using the same for inhibiting or downregulating CFB gene expression.
Core Innovation
The disclosure describes chemically modified, GalNAc-conjugated small interfering RNAs targeting complement factor B (CFB) mRNA to promote degradation and reduce CFB expression. The duplex incorporates defined antisense and sense strands with 2′-O-methyl, 2′-F, phosphorothioate linkages, and GalNAc G1b moieties for targeted delivery. The disclosure further encompasses vectors, delivery systems, pharmaceutical compositions, and methods for therapeutic CFB downregulation.
Reported screening results demonstrate potent, dose-dependent complement factor B knockdown across cellular systems and animal models. In cynomolgus monkeys, the siRNA decreases serum CFB protein by up to 98% and alternative complement pathway activity by up to 99.8%, sustaining suppression through day 84. In human-CFB transgenic mice, the treatment markedly suppresses serum CFB protein and liver CFB mRNA levels.
Claims Coverage
The relevant claims identify one independent claim across four inventive features covering modified siRNA, formulations, therapeutic treatment, and target downregulation.
Modified CFB-targeting siRNA
The independent claim recites a small interfering RNA directed to complement factor B (CFB) comprising defined antisense and sense strands with 2′-O-methyl and 2′-F modifications, phosphorothioate linkages, and GalNAc G1b moieties.
Pharmaceutical composition
The claims specify a pharmaceutical composition comprising the claimed siRNA and a pharmaceutically acceptable carrier, diluent, or excipient.
Treatment of CFB-associated disease
The claims describe administering the siRNA to treat a disease or disorder associated with increased CFB expression or activity, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries, multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosus, C3 glomerulonephritis, atypical hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica spectrum disorder, dense deposit disease, age-related macular degeneration, IgA nephropathy, multifocal motor neuropathy, organ transplantation, and neurodegenerative diseases.
Downregulation of CFB
The claims describe administering the claimed siRNA to downregulate CFB expression or level.
The claims focus on a chemically modified, GalNAc-conjugated CFB-targeting siRNA and encompass pharmaceutical formulations, downregulating CFB, and treating CFB-associated conditions.
Stated Advantages
The reported screening results show potent, dose-dependent CFB knockdown, reducing serum CFB protein by up to 98% and alternative-pathway activity by up to 99.8% in cynomolgus monkeys, with substantial suppression through day 84.
In human-CFB transgenic mice, high-dose treatment reduces serum CFB protein by 94.2% and liver CFB mRNA by 85% at day 56.
The described GalNAc-mediated targeting and modified features are intended to improve delivery, stability, potency, or duration.
Documented Applications
Treatment of diseases or disorders associated with increased CFB expression or activity, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries, multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosus, C3 glomerulonephritis, atypical hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica spectrum disorder, dense deposit disease, age-related macular degeneration, IgA nephropathy, multifocal motor neuropathy, organ transplantation, and neurodegenerative diseases.
Downregulation of CFB expression or level using the claimed siRNA.
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