Age-related macular degeneration (AMD) is a slowly progressing disease involving genetic abnormalities and environmental insults. It is the leading cause of blindness for older Americans; and as the population ages, the prevalence of AMD continues to grow. Since smoking increases AMD risk and there is a higher incidence of smoking in veterans, disproportionally more veterans will be affected. Treatments are available for choroidal neovascularization (CNV); but those come with risks and only target a subpopulation of AMD patients. No treatment is available for early AMD and geographic atrophy (GA; >85% of all cases), making it paramount to develop a treatment for early disease intervention. While mechanistic studies have shown that inflammation and smoking are fundamental components of AMD, genetic studies have demonstrated that polymorphisms in complement proteins each increase the risk for developing AMD. One of the most detri- mental mutation occurs in factor H (fH) an essential inhibitor in the complement alternative pathway (AP), suggesting that inadequate control of complement-driven inflammation is a major AMD risk factor. To date, complement therapeutics in GA have not been FDA approved. Approaches included blocking complement factor C3 and C5 (activators in the terminal pathway) or factor D (fD; AP activator). What these strategies had in common was that most of the drug was wasted on non-pathophysiologically important target mole- cules; i.e., most complement components in fluids or tissue are not engaged in complement activation and hence to reduce complement activation at the ocular target sites [basal RPE, Bruch’s membrane (BrM) or choriocapillaris (CC)], the majority of a given complement component has to be permanently inhibited to achieve the desired effect. In addition, complement components are made in the eye and systemically, and many complement components can penetrate BrM; hence an almost unlimited reservoir of complement pro- teins exists that needs to be controlled. Given these complications, we propose to build on our data utilizing an “addressable” inhibitor that target to sites of complement activation regardless of the location (CR2-fH) delivered via gene therapy, as well as antibody to monitor complement activation. First, we will utilize hu- man iPSC-RPE cells to examine efficacy of AAV-CR2-fH in complement-mediated RPE pathology, focusing on control and cells with AMD genetic risk factors, assaying complement activation and deposit formation. Second, both diagnosis and monitoring of efficacy of treatment would benefit from in vivo tools to monitor complement activation. We have developed tools (antibodies and nanobodies) as well as fluorescence quenched C3 convertase-specific substrate for monitoring of complement activation in tissues and ocular fluids, which will be tested in animals and iPSC-RPE cultures. Overall, this work is designed to move anti- complement therapy towards clinical application, with the long-te...