Diabetic retinopathy and age-related macular degeneration (AMD) are two leading causes of blindness in the Western countries. What these two diseases have in common is ocular neovascularization (angiogenesis), which is also involved in other retinopathies. Neovascularization is mainly caused by vascular endothelial growth factor (VEGF) that is produced by retinal pigment epithelial (RPE) cells. VEGF is induced by hypoxia-inducible factor (HIF-1), a transcription factor that is stabilized by hypoxia. In addition, insulin and insulin-like growth factor (IGF-1) have a causative role in retinal neovascularization and diabetic retinopathy. Insulin induces HIF-1 in RPE cells, rendering such cells angiogenic. We have shown that insulin dramatically induces a HIF-1-responsive luciferase construct (HRE-Luc) transiently transfected into RPE cells. This induction is completely blocked by inhibitors of the insulin/PI3-K signaling pathway. This provides a rationale for drug discovery. The first aim is to develop a simple technology, based on the HIF-1-mediated luciferase assay, to screen for inhibitors of the insulin-induced response in RPE cells. This technology might be further licensed to pharmacological companies to develop new agents for therapy of diabetic retinopathy and AMD. The second aim is to screen a 2000-compound library of currently approved and known drugs. This may allow us to develop old drugs for a novel use, by formulating the drugs as eye drops (composition of matter) for prevention of insulin-induced retinopathy. This Phase I STTR application is aimed at development the technology for a drug screen and using this technology to identify inhibitors of mitogen/insulin-activated angiogenic response. These agents can be further developed for therapy of diabetic retinopathy, age-related macular degeneration, tumor-associated angiogenesis, and other disorders associated with neovascularization. Given that initial screen will be performed using the collection of known drugs, we expect that this will have an immediate impact on the development of new drug formulations and the therapy of patients
