PT - JOURNAL ARTICLE AU - Chew, Lindsey A. AU - Grigsby, Daniel AU - Hester, C. Garren AU - Amason, Joshua AU - McPherson, W. Kyle AU - Flynn, Edward J. AU - Visel, Meike AU - Flannery, John G. AU - Rickman, Catherine Bowes TI - Truncated Complement Factor H Y402 Gene Therapy Cures C3 Glomerulonephritis AID - 10.1101/2024.09.17.613471 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.09.17.613471 4099 - http://biorxiv.org/content/early/2024/09/21/2024.09.17.613471.short 4100 - http://biorxiv.org/content/early/2024/09/21/2024.09.17.613471.full AB - Patients with both age-related macular degeneration (AMD) and C3 glomerulonephritis (C3G) are challenged by the absence of effective therapies to reverse and eliminate their disease burden. Capitalizing on complement dysregulation as both a significant risk factor for AMD and the known pathophysiology of C3G, we investigated the potential for adeno-associated virus (AAV) delivery of complement factor H (CFH) to rescue C3G in a Cfh-/- mouse model of C3G. While past efforts to treat C3G using exogenous human CFH resulted in limited success before immune rejection led to a foreign protein response, our findings demonstrate the capacity for long-term AAV-mediated delivery of truncated CFH (tCFH) to restore inhibition of the alternative pathway of complement and ultimately reverse C3G without immune rejection. Comparing results from the administration of several tCFH vectors also revealed significant differences in their relative efficiency and efficacy. These discoveries pave the way for subsequent development of AAV-mediated tCFH replacement therapy for patients with C3G, while simultaneously demonstrating proof of concept for a parallel AAV-mediated tCFH gene augmentation therapy for patients with AMD.Competing Interest StatementC. Bowes Rickman: Applied Genetic Technologies Corporation (F), Aevitas Therapeutics (F), 4DMT (C).