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C3 glomerulopathy (C3G) is characterized by hyperactivation of alternative pathway (AP) complement activation as a result of C3 nephritic factors and/or mutations in complement genes. Complement factor H deficient (CFH−/−) mice have been a mainstay for experimental studies to understand the mechanisms underlying C3G. However, end-stage renal disease (ESRD) can take several months to manifest in CFH−/− mice, requiring long preclinical studies to assess new therapeutics. Alternative C3G models, in multiple species, can be quite useful. Two novel genetic models of C3G, developed at Regeneron, and enabled by Velocigene® technology are described here.(1) Dysregulated complement activation by replacing mouse C3 gene with human C3 (C3 hu/hu) in mice: The C3G phenotype in C3 hu/hu mice may emerge from a lack of interaction between human C3 protein and multiple mouse complement …