NM_000186.4(CFH):c.1873G>T (p.Glu625Ter)

For the rare, highly penetrant CFH c.1873G>T (p.Glu625Ter) nonsense variant — which eliminates the C-terminal complement C3b/polyanion-binding domains essential for local complement regulation on retinal surfaces — subretinal AAV-mediated delivery of a functional CFH transgene represents a rational gene supplementation strategy. Unlike the common CFH Y402H risk variant (which modestly increases AMD risk in a polygenic context), this loss-of-function variant causes severe complement dysregulation and may respond to gene replacement restoring local CFH expression in the RPE/subretinal space.

Complement Factor H (CFH) is the principal fluid-phase and surface-bound regulator of the alternative complement pathway. It contains 20 short consensus repeat (SCR) domains; the C-terminal SCR19-20 domains mediate binding to host cell surfaces via C3b and glycosaminoglycans. The p.Glu625Ter variant truncates CFH within SCR10, eliminating SCR11-20 and ablating surface-recognition capacity while potentially preserving some fluid-phase C3b cofactor activity (SCR1-4). Gyroscope Therapeutics (now Novartis) developed GT005, a subretinal AAV2-based vector expressing Complement Factor I (CFI, a related complement regulator), which completed Phase I/II trials (NCT03846193) for geographic atrophy AMD. An analogous approach delivering CFH directly to RPE cells could restore local complement regulation at Bruch membrane, where complement activation drives drusen formation and RPE atrophy. Apellis pegcetacoplan (Syfovre, intravitreal C3 inhibitor) and Iveric Bio avacincaptad pegol (Izervay, intravitreal C5 inhibitor) are approved complement-targeted therapies for GA, validating complement as a druggable pathway in AMD.

Most AMD is polygenic with small effect sizes from multiple complement and non-complement loci — gene therapy targeting CFH alone may not suffice for typical AMD. However, the p.Glu625Ter variant is a rare, high-impact allele where monogenic complement dysregulation is the primary driver, making it a better candidate for gene replacement than common-variant AMD. AAV-CFH transgene must produce secreted CFH that reaches the subretinal/Bruch membrane compartment at sufficient concentrations. CFH is a large protein (155 kDa, ~3.7 kb CDS), which fits within AAV capacity but leaves limited room for regulatory elements. No clinical trial specifically testing AAV-CFH gene delivery for AMD has been registered. The natural history of CFH loss-of-function variants in AMD is not as well characterized as for atypical hemolytic uremic syndrome (aHUS), where CFH mutations are better studied.