Small interfering RNA targeting C3 and uses thereof
Inventors
ZHANG, Chunyang • Geng, Xin • Wang, Shiyu • Wang, Weimin
Assignees
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Publication Number
US-12703865-B2
Publication Date
2026-08-11
Expiration Date
Abstract
This disclosure relates to isolated oligonucleotides comprising duplex regions targeting human complement C3 mRNA, and delivery systems, kits and compositions comprising the same, and methods of using the same for inhibiting or downregulating C3 gene expression.
Core Innovation
The disclosure describes an isolated double-stranded oligonucleotide targeting complement C3 mRNA, comprising an antisense strand identified as SEQ ID NO: 451 and a sense strand identified as SEQ ID NO: 444. The oligonucleotide incorporates 2′-O-methyl and 2′-F modifications, phosphorothioate internucleotide linkages, and GalNAc G1b moieties at the 3′ end of the sense strand. These chemical modifications facilitate complement C3 mRNA degradation and provide liver-directed uptake.
The disclosure further describes delivery systems, vectors, and pharmaceutical compositions containing the isolated oligonucleotide with a pharmaceutically acceptable carrier, diluent, or excipient. Evaluations demonstrate reduction of complement C3 mRNA across cell and animal models, alongside circulating serum C3 protein reductions. Additional configurations include modified backbone linkages and 5′-terminal phosphate mimics intended to improve Ago2 loading and metabolic stability.
Claims Coverage
The claims recite three inventive features across independent claims 1, 4, and 7, which cover an isolated oligonucleotide targeting complement C3 defined by specific sequences and chemical modifications.
Oligonucleotide comprising specified strands
Claim 1 covers an isolated oligonucleotide comprising an antisense strand comprising SEQ ID NO: 451 and a sense strand comprising SEQ ID NO: 444, with 2′-O-methyl and 2′-F modifications, phosphorothioate internucleotide linkages, and GalNAc G1b moieties. Dependent claims add delivery-system formats or pharmaceutical compositions.
Oligonucleotide comprising strands consisting of specified sequences
Claim 4 covers an isolated oligonucleotide comprising an antisense strand and a sense strand, each consisting of the nucleic acid sequences identified as SEQ ID NO: 451 and SEQ ID NO: 444, with 2′-O-methyl and 2′-F modifications, phosphorothioate internucleotide linkages, and GalNAc G1b moieties. Dependent claims add delivery-system formats or pharmaceutical compositions.
Oligonucleotide consisting of specified strands
Claim 7 covers an isolated oligonucleotide consisting of an antisense strand and a sense strand, each consisting of the nucleic acid sequences identified as SEQ ID NO: 451 and SEQ ID NO: 444, with 2′-O-methyl and 2′-F modifications, phosphorothioate internucleotide linkages, and GalNAc G1b moieties. Dependent claims add delivery-system formats or pharmaceutical compositions.
The three independent claims define the C3-targeting oligonucleotide and its chemical modifications across varying comprising or consisting scope, supported by dependent claims covering delivery systems and pharmaceutical compositions.
Stated Advantages
The disclosed oligonucleotides attenuate C3 expression and induce complement C3 mRNA degradation, demonstrating reductions in complement C3 mRNA in cell and animal models and reductions in circulating serum C3 protein.
GalNAc G1b targeting-ligand conjugation provides liver-directed uptake.
The described 5′-terminal phosphate mimics are intended to improve Ago2 loading and metabolic stability.
Documented Applications
Targeting C3 mRNA to achieve C3 mRNA silencing, expression attenuation, and treatment of C3-associated diseases and disorders.
Liver-directed uptake using GalNAc G1b targeting-ligand conjugation.
Formulation into delivery systems, including liposomes, nanoparticles, polymer-based systems, ligand-conjugate systems, and vectors.
Formulation into pharmaceutical compositions with a pharmaceutically acceptable carrier, diluent, or excipient.
Reduction of complement C3 mRNA in Huh-7 cells, mouse liver models, primary human hepatocytes, and cynomolgus macaques, as well as reduction of serum C3 protein in cynomolgus macaques.
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