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. Despite the many encouraging data in animal models and early phase clinical trials, complement therapeutics in GA to date have failed to reach clinical endpoints in phase 2/3 trials. Approaches included blocking complement factor C5 (activator 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 molecules; i.e., most complement components in fluids or tissue are not engaged in complement activation and hence to reduce complement activation for example at the RPE, Bruch?s membrane (BrM) or choriocapillaris (CC), the majority of a given complement component has to be permanently inhibited to achieve the desired ef- fect. 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 proteins exists that needs to be controlled. Finally, it is still unclear what is the tissue of complement activation in dry AMD; reti- na, RPE, BrM or CC. Given these complications, we propose to build on our preliminary data utilizing an ?addressable? inhibitor that target to sites of complement activation regardless of the location (CR2-fH) de- livered via gene therapy. We will determine the site of delivery, intravitreal, subretinal or suprachoroidal, re- quired for optimal protection, the time window of delivery, and confirm efficacy in animal models of AMD. Specifically, vectors are designed to optimally target cells in the inner retina, RPE and choroid and tested for efficacy in two validated mouse models (choroidal neovascularization and smoke-induced ocular pathol- ogy). The optimal vectors will be confirmed in additional mouse and non-human primate models. Overall, this work is designed to move anti-complement therapy towards clinical application, with the long-term goal of developing a treatment to reduce the number of AMD cases and improve veteran care and quality of life.

Public Health Relevance

Age-related macular degeneration (AMD) is thought to involve an overactive complement system in the posterior pole of the eye. We have developed and validated a targeted AP inhibitor as a possible therapeutic agent for the treatment of AMD using both protein and delivery using AAV vector therapy. Here we will determine the site of delivery, intravitreal, subretinal or suprachoroidal, required for optimal protection, the time window of delivery, and confirm efficacy in animal models of AMD.

National Institute of Health (NIH)
Veterans Affairs (VA)
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Sensory Systems & Communication Disorders (RRD3)
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Ralph H Johnson VA Medical Center
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