Abstract 6848: Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy

Abstract C3 glomerulopathy (C3G) is a rare and progressive kidney disease, encompassing C3 glomerulonephritis and dense deposit disease, both driven by dysregulation of the alternative pathway of complement activation. Approximately 50% of patients progress to end-stage kidney disease (ESKD) within 10 years, with limited treatment options currently available. To address this unmet need, we developed a novel humanized C3 (hC3) mouse model that exhibits a pronounced C3G-like phenotype, characterized by early progression to ESKD and increased mortality. Compared to wild-type mice, hC3 mice display significantly reduced circulating C3 levels, alongside liver and kidney dysfunction confirmed by biochemical and pathological analyses. These mice also demonstrate reduced body weight, elevated morbidity early in life, and a shortened lifespan of approximately 5-6 months. To evaluate potential therapies, we treated hC3 mice with the small interfering RNA drug ARO-C3 at high and low doses. ARO-C3 treatment led to a reduction in serum hC3 levels as early as one week post-administration, with a single dose maintaining suppression for at least five weeks. Importantly, ARO-C3 treatment significantly prolonged survival and improved liver and kidney function, as demonstrated by molecular and histopathological analyses. This hC3 mouse model provides a robust platform for studying complement-mediated diseases such as C3G and for preclinical evaluation of novel therapeutic strategies targeting the complement system. Citation Format: Andrei Golovko, Shuang Li, Xiaolei Qiu, Yi Li, Ruilin Sun. Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6848.