Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

Significance Statement C3 glomerulopathy (C3G) is a rare, progressive kidney disease, characterized by alternative pathway hyperactivation and glomerular complement deposition. Animal models are valuable to explore modulators of C3G progression. A severe C3G mouse model was developed by replacing the mouse C3 gene with the human equivalent. The humanized C3 mice mimic pathologic features of patients with C3G, potentially due to dysregulated interaction of human C3 protein with mouse complement regulators. A C5-blocking antibody showed that C5 dominates pathogenesis of humanized C3 mice. C3b- and complement factor B–blocking antibodies provide benefit, indicating that alternative-pathway hyperactivation drives pathology in these mice. The humanized model exhibits rapid, severe renal disease, offering the opportunity to genetically and pharmacologically dissect critical contributors to complement-driven renal pathology. Background C3 glomerulopathy (C3G) is characterized by the alternative-pathway (AP) hyperactivation induced by nephritic factors or complement gene mutations. Mice deficient in complement factor H (CFH) are a classic C3G model, with kidney disease that requires several months to progress to renal failure. Novel C3G models can further contribute to understanding the mechanism behind this disease and developing therapeutic approaches. Methods A novel, rapidly progressing, severe, murine model of C3G was developed by replacing the mouse C3 gene with the human C3 homolog using VelociGene technology. Functional, histologic, molecular, and pharmacologic assays characterize the presentation of renal disease and enable useful pharmacologic interventions in the humanized C3 (C3 hu/hu ) mice. Results The C3 hu/hu mice exhibit increased morbidity early in life and die by about 5–6 months of age. The C3 hu/hu mice display elevated biomarkers of kidney dysfunction, glomerulosclerosis, C3/C5b-9 deposition, and reduced circulating C3 compared with wild-type mice. Administration of a C5-blocking mAb improved survival rate and offered functional and histopathologic benefits. Blockade of AP activation by anti-C3b or CFB mAbs also extended survival and preserved kidney function. Conclusions The C3 hu/hu mice are a useful model for C3G because they share many pathologic features consistent with the human disease. The C3G phenotype in C3 hu/hu mice may originate from a dysregulated interaction of human C3 protein with multiple mouse complement proteins, leading to unregulated C3 activation via AP. The accelerated disease course in C3 hu/hu mice may further enable preclinical studies to assess and validate new therapeutics for C3G.