Humanized C3 Mouse: A Novel Accelerated Model Of C3 Glomerulopathy

Background C3 glomerulopathy (C3G) is characterized by the alternative-pathway (AP) hyperactivation induced by nephritic factors or complement genemutations. 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 comparedwithwild-typemice. Administration of a C5-blockingmAb 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 consistentwith 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.