Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness worldwide. Wet AMD (wAMD) is the primary type of AMD leading to blindness, characterized by rapid vision loss due to neovascularization. Currently, the primary treatment for wAMD relies on anti-vascular endothelial growth factor (VEGF) drugs. However, some patients respond poorly to this therapy, suggesting a complex pathogenesis that necessitates the exploration of multi-target therapeutic strategies. Recent studies have revealed that aberrant activation of the complement system plays a crucial role in the development of wAMD. Specifically, molecules such as C3, C5, C3a, C5a, and the membrane attack complex (MAC) are involved in the formation of choroidal neovascularization (CNV) by modulating VEGF and other inflammatory factors. Genetic studies have confirmed a strong association between mutations in complement-related genes and wAMD, such as CFH and C3. Furthermore, animal experiments support the therapeutic potential of complement inhibitors in treating CNV. Currently, clinical trials targeting complement components like C3, C5, and MAC are underway, with some drugs having advanced to phase Ⅱ/Ⅲ clinical studies. However, their efficacy requires further validation. In the future, complement-targeted therapy, particularly in combination with anti-VEGF treatment, is poised to become a new direction in wAMD management, potentially offering superior therapeutic options for patients.
Geographic atrophy (GA), the late-stage of non-neovascular age-related macular degeneration, is characterized by progressive degeneration of photoreceptors, retinal pigment epithelium, and the choriocapillaris, ultimately leading to irreversible central vision loss. Advances in multimodal imaging, particularly the optical coherence tomography (OCT) based definition of complete retinal pigment epithelium and outer retinal atrophy (cRORA), have substantially improved the diagnostic consistency of GA. The recent approval of complement inhibitors, pegcetacoplan (complement C3 inhibitor) and avacincaptad pegol (complement C5 inhibitor) marks a treatment milestone, demonstrating efficacy in slowing atrophy progression. However, the efficacy of existing drugs still mainly focuses on structural endpoints, with limited protective effects on functions. This reveals the core challenge of "structural-function dissociation" in GA. In recent years, attention has been drawn to early endpoints such as incomplete retinal pigment epithelium and outer retinal atrophy transforming into cRORA; sensitive functional assessment tools such as micro-perimetry, as well as artificial intelligence-assisted OCT stratified analysis and individualized progression prediction models, have also continuously expanded the assessment and management capabilities of GA. Additionally, diverse treatment strategies such as gene therapy, stem cell transplantation, and neurotrophic protection are also being actively explored, further broadening the future intervention pathways. It is worth noting that the prevalence and clinical manifestations of GA in Asian populations are significantly different from those in Western populations, suggesting that the disease characteristics and mechanisms may have racial specificity. Currently, there is a lack of systematic local data in China, and it is urgent to establish a multicenter longitudinal cohort based on cRORA criteria, and incorporating multimodal imaging and functional assessments, to facilitate GA characterization, risk prediction, and the development of individualized intervention strategies in the Chinese population.
