Project Summary Neovascular age-related macular degeneration (nAMD) with choroidal neovascularization (CNV) is a leading cause of vision loss in elderly Americans and is currently treated by anti-angiogenic drugs against vascular endothelial growth factor (VEGF) with limited efficacy. While anti-VEGF drugs are widely used as the first-line therapy for nAMD, more than half of treated patients develop subretinal fibrosis (SRF) or scar that disrupts retinal function and hinders visual acuity improvement with unknown causes. Anti-VEGF therapy has a paradoxical role in fibrosis of other diseases with poorly defined mechanisms. Likewise, the causal link between anti-VEGF therapy and SRF remains elusive but is of profound importance to mitigate the new epidemic and save the vision for nAMD patients. The objective of this project is to investigate mechanisms of Janus-faced anti-VEGF therapy in SRF of CNV and develop novel dual anti-angiogenesis and anti-fibrosis therapy. The central hypothesis is that inhibition of angiogenesis by anti-VEGF drugs during early stages of CNV alleviates SRF, whereas anti- VEGF therapy at late stages of the disease exacerbates SRF. In Aim 1, we will investigate anti-VEGF therapy at early and late stages of CNV in different animal models to test the central hypothesis. In Aim 2, we will investigate whether two novel VEGF-independent anti-angiogenic therapies possess dual anti-CNV and anti- fibrosis activity at any stage of the disease. In Aim 3, we will characterize combination therapy of anti-VEGF drug with novel VEGF-independent anti-angiogenic inhibitors to synergistically alleviate CNV and SRF via different receptor signaling pathways. The successful implementation of this project will confirm the causal link between anti-VEGF therapy and SRF and provide a clinical strategy to mitigate the emerging epidemic by limiting anti- VEGF therapy to early stages of the disease. This may help reduce SRF in nAMD patients and improve visual acuity. Furthermore, this study will also develop first-in-class dual anti-angiogenesis and anti-fibrosis therapies to circumvent the emerging epidemic of anti-VEGF-induced SRF.