GA, a leading cause of blindness, is strongly associated with genes that regulate the alternative complement pathway (AP). Complement overactivation in the choroidal compartment can be observed before the onset of GA. Poor regulation of the amplification loop results in generation of the potent opsonin C3b leading to inflammation, membrane attack complex (MAC) formation, RPE/photoreceptor cell death and vision loss. Inhibitors of the AP have shown modest efficacy to date with no vision preservation following 2 years of treatment. There is growing appreciation of the need for treatments to address complement overactivation in both retinal and choroidal compartments, separated by Bruch’s membrane (BrM).

Complement Therapeutics is developing CTx001, an AAV gene therapy encoding a novel soluble protein (mini-CR1) derived from complement receptor 1 (CR1), for the treatment of GA. We show that mini-CR1 retains potent co-factor activity enabling rapid Factor I (FI) mediated cleavage of C3b with IC₅₀ of 125nM. Importantly, we show mini-CR1 supports cleavage of C3b to C3dg in contrast to Factor H (FH) and FHL-1 that cleave only to iC3b at physiological conditions. Like C3b, iC3b is a potent opsonin. Mini-CR1 can traverse human BrM ex vivo unlike FI and FH. Mini-CR1 expression in murine eyes following subretinal CTx001 was dose proportionate, and in the laser CNV model, MAC formation was reduced by 69% relative to null vector.

CTx001 is a potent AP regulator with a highly differentiated profile and in vivo findings suggest it is well tolerated and pharmacologically active. Continued development is therefore warranted.