The role of complement membrane attack complex in dry and wet AMD - From hypothesis to clinical trials

Data from human dry and wet age-related macular degeneration (AMD) eyes support the hypothesis that constant ‘tickover’ of the alternative complement pathway results in chronic deposition of the complement membrane attack complex (MAC) on the choriocapillaris and the retinal pigment epithelium (RPE). Sub-lytic levels of MAC lead to cell signaling associated with tissue remodeling and the production of cytokines and inflammatory molecules. Lytic levels of MAC lead to cell death. CD59 is a naturally occurring inhibitor of the assembly of MAC. CD59 may thus be therapeutically efficacious against the pathophysiology of dry and wet AMD. The first gene therapy clinical trial for geographic atrophy - the advanced form of dry AMD has recently completed recruitment. This trial is studying the safety and tolerability of expressing CD59 from an adeno-associated virus (AAV) vector injected once into the vitreous. A second clinical trial assessing the efficacy of CD59 in wet AMD patients is also under way. Herein, the evidence for the role of MAC in the pathophysiology of dry as well as wet AMD and the scientific rationale underlying the use of AAV- delivered CD59 for the treatment of dry and wet AMD is discussed. •Complement is activated in AMD.•The Membrane Attack Complex is chronically deposited on the choriocapillaris and RPE but is at higher levels in AMD patients.•The MAC leads to regression of the choriocapillaris and death of RPE in AMD patients.•CD59 can block the formation of MAC.•The safety and efficacy of an adeno-associated virus expressing CD59 is being evaluated in dry and wet AMD patients.