Complement Inhibition for Geographic Atrophy: A Tempting Target with Mixed Results

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. One of the strongest genetic risk factors for AMD is a complement factor H (CFH) gene polymorphism characterized by a tyrosine-histidine change at amino acid position 402 (Y402H). The magnitude of this association between the Y402H variant and AMD is among the strongest that has been identified for any complex, multifactorial human disease. This strong association has motivated researchers to investigate a potential link between various elements of the complement pathway and AMD pathogenesis. Given the possible contribution of complement dysregulation to AMD, complement inhibition has emerged as a therapeutic strategy for slowing geographic atrophy (GA). Randomized clinical trials thus far have yielded mixed results. In this article, we provide the historical context for complement inhibition as a strategy for treating GA, discuss potential advantages and disadvantages of complement inhibition, and highlight the questions that must be addressed before complement inhibition can take center stage as a therapy for AMD.