SUMMARY Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the U.S. Wet AMD accounts for up to 90% of vision loss in AMD patients, which is characterized by choroidal neovascularization (CNV). Currently, no cure exists for AMD, and available drug therapies focus on intravitreal injection of anti- vascular endothelial growth factor (VEGF) agents. These anti-VEGF drugs have achieved impressive therapeutic effects on CNV in approximately 70% of AMD patients; however, the other 30% of patients remain unresponsive to anti-VEGF therapies. AMD is a multi-factorial disease，therapies that only target a single molecule (such as VEGF) do not benefit for all patients with AMD. Therefore, the development of new drugs to target multiple pathogenic factors with a single compound, is an unmet clinical need. Peroxisome proliferator-activated receptor α (PPARα) is a widely expressed, ligand-activated transcriptional factor. Recent studies provide strong evidence supporting that PPARα agonist could suppress the vicious cycle of chronic inflammation in the RPE and retina, a key cause in the pathogenesis of AMD. In addition, clinical studies have demonstrated that oral treatment of fenofibrate (an agonist of PPARα) could significantly reduce the need of laser photocoagulation for retinal neovascularization by 37-40%. PPARα agonist inhibits neovascularization and overproduction of multiple inflammatory factors in AMD animal models. Meanwhile, as small molecules, PPARα agonists can penetrate through the blood-retinal barrier, making it a promising novel oral option for the prevention and treatment of AMD. However, fenofibrate’s low specificity, low potency, and dose-limiting toxicities make it a non-ideal treatment option for AMD. Recently, our team has independently designed, synthesized, and screened more than 200 new PPARα agonists, from which we identified a novel non-fibrate compound A190, with significantly improved potency and selectivity for PPARα agonism (EC50 = ∼37 nM). It activates PPARα and upregulates expression of PPARα target genes in retinal cells, and confers anti-angiogenic and anti-inflammatory, and neuroprotective effects superior to fenofibrate. It also reduces retinal inflammation and vascular leakage in AMD models. We will evaluate the effects of A190 on retinal NV and inflammation in AMD animal models. The project will be achieved by two specific aims. Specific Aim 1: Determine whether A190 suppresses subretinal NV. Specific Aim 2: Determine whether A190 inhibits oxidative stress/inflammation. The proposed studies will prove the therapeutic effect of this compound on AMD models and will lay a solid ground for further PK, toxicity, mechanism studies in future Phase II project.