CELL BASED OCULAR DELIVERY OF ANTIANGIOGENICS FOR PDR

Scripps Research Institute, La Jolla CA

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Abstract

The prevalence of diagnosed and undiagnosed diabetes mellitus in U.S. adults is estimated to be 6 percent. A significant complication in these individuals is diabetic retinopathy (DR); a condition that accounts for 12 percent of all new cases of blindness in Americans each year and afflicts more than 90 percent of all individuals with diabetes of longer than 20 years duration. DR is characterized, in its advanced stages, by uncontrolled proliferation of abnormal, new blood vessels and associated extracellular matrix; this stage is called proliferative diabetic retinopathy (PDR). Recent advances in the fields of integrin biology and the extracellular matrix have converged to provide novel insight into the underlying mechanisms involved in the angiogenic process. While it would not necessarily cure the underlying diabetic condition, a better understanding of angiogenesis would significantly enhance our abilities to design drugs that could effectively inhibit this process and prevent the visually disastrous complications that are associated with uncontrolled ocular neovascularization in PDR. As vascular endothelial cells are stimulated to proliferate they must navigate the extracellular matrix and do so by selectively displaying the integrins avb3 and avb5 on their surface. At least one of these integrins, avb3, can bind to matrix metalloproteinase-2 (MMP-2) which, in turn, can facilitate the degradation of surrounding matrix thus facilitating endothelial cell migration and blood vessel proliferation. MMP-2 itself is then cleaved, generating a carboxy terminal fragment that can bind to avb3 but lacks proteolytic activity. By preventing binding of full length, catalytically active MMP-2, this MMP-2 fragment, known as PEX, can inhibit angiogenesis. In this program cell-based delivery systems will be used to (1) establish a model of retinal fibrovascular proliferation and (2) determine the efficacy of PEX as an anti-angiogenic. The cell-based delivery system consists of cells expressing a transgene product that are encapsulated in hollow fiber membrane devices of varying porosity. Local delivery in the eye of naturally occurring anti-angiogenic compounds such as PEX would potentially provide a non-destructive treatment modality for PDR.