Therapeutic Evaluation of a C3-Targeting Small Nucleic Acid Drug in a Spontaneous Humanized C3 Glomerulopathy Mouse Model 2256845

Abstract Introduction Complement component C3 is central to the activation of the alternative pathway (AP), and its dysregulation drives C3 glomerulopathy, a severe renal autoimmune disease that lacks effective therapies. Methods To enable translational studies, we established a humanized C3G model, B6-hC3 mC3 KO, which overexpresses human C3 while lacking the endogenous murine C3. These mice spontaneously develop progressive glomerulopathy resembling human C3G pathology. Small nucleic acid drugs were administered to mice to evaluate drug efficacy. Results The disease phenotype observed in humanized C3 transgenic mice appears to arise from a dysfunctional interaction between human C3 protein and murine complement proteins, resulting in uncontrolled AP activation. Subcutaneous administration of C3-targeting small nucleic acid drugs effectively reduced serum C3 and plasma C3a levels, and downregulated the ratio of Ba (the activated fragment of complement factor B, CFB) to CFB, indicating suppression of AP hyperactivation. After 6 weeks of treatment, renal histology showed markedly reduced deposition of hC3 and diminished inflammatory cell infiltration. Conclusion B6-hC3 mC3 KO mice reproduce key immunopathological features of C3G and serve as a powerful platform for mechanistic studies and preclinical evaluation of complement-targeted therapeutics. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)