Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists

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DESCRIPTION (provided by applicant): Despite the near-universal skepticism that initially greeted Folkman's presentation of his idea that anti-angiogenesis would be an effective approach to cancer chemotherapy, this concept has now become widely accepted and forms a basis not only for cancer therapy, but also for therapy of a broad range of non-neoplastic disorders that Folkman summarizes under the term 'angiogenesis-dependent diseases'. Currently approved therapies, directed against the central bodily chemical involved in angiogenesis, VEGF, are useful, but not entirely safe or effective. We propose to develop new anti-VEGF agents through discovery by powerful phage display methods, and to apply these new agents as a forthcoming generation of safe and effective angiogenesis inhibitors. Our specific aims are: (i) to discover and develop new anti-angiogenic peptidomimetic compounds targeting the VEGF receptor family, and (ii) to design and test new agents for therapeutic control of retinal angiogenesis. These agents would both bind selectively to pathological new blood vessels and block or destroy them, without affecting normal blood vessels. Our goal is to understand and inhibit pathological angiogenesis in the neural retina of experimental mouse models of human blindness-causing diseases. PUBLIC HEALTH RELEVANCE:This study will, in time, extrapolate to treatment, diagnosis and therapy of two major retinal vascular diseases responsible for blindness in the U.S. and throughout the world, for which we have good experimental models - retinopathy of prematurity and age-related macular degeneration. Blood vessels are essential bodily components that deliver oxygen and nutrients to almost all organs and tissues. Most vessels are formed during embryonic development, and in adults the formation of new blood vessels (a process called angiogenesis) is limited, mainly during wound healing and the normal female reproductive cycle. This creates an opportunity for therapy, as several diseases can progress only if they induce the formation of new blood vessels; cancer, obesity, diabetes, asthma, arthritis, cirrhosis, and ocular diseases are among the many illnesses likely to be slowed down or blocked by the development of angiogenesis inhibitors. Our goal in this proposal is to understand and prevent the pathological angiogenesis process in experimental models for diseases of the retina while sparing normal angiogenesis, with the expectation that the results will, in time, extrapolate to new treatment regimens and therapy for the two major retinal vascular diseases causing blindness in the U.S. for which we have good experimental models - retinopathy of prematurity and age-related macular degeneration.