CELL BASED OCULAR DELIVERY OF ANTIANGIOGENICS FOR PDR

美国已诊断和未诊断糖尿病的患病率 成人估计为6%。 一个重要的并发症， 糖尿病视网膜病变（DR）是一种 占美国所有新失明病例的12%， 超过90%的糖尿病患者都患有这种疾病 持续时间超过20年。 DR的特点是先进的 阶段，不受控制的增殖异常，新的血管和 相关的细胞外基质;这个阶段称为增殖 糖尿病视网膜病变（PDR）。 整合素研究进展 生物学和细胞外基质已经会聚，以提供新的 深入了解参与血管生成的潜在机制， 过程 虽然它不一定能治愈潜在的糖尿病 条件下，更好地了解血管生成将显着 增强我们设计药物的能力， 这一过程，并防止视觉灾难性的并发症， 与PDR中不受控制的眼部新生血管形成相关。 作为 血管内皮细胞被刺激增殖，它们必须 通过选择性地展示细胞外基质 整合素AVB 3和AVB 5在它们的表面上。 至少一种这些 整联蛋白avb 3可以与基质金属蛋白酶-2（MMP-2）结合， 反过来，可以促进周围基质的降解， 促进内皮细胞迁移和血管增殖。 然后MMP-2本身被切割，产生羧基末端片段 其可结合AVB 3但缺乏蛋白水解活性。 通过防止 结合全长催化活性MMP-2，该MMP-2片段， 称为PEX，可以抑制血管生成。 在这个程序中， 递送系统将用于（1）建立视网膜的模型， 纤维血管增殖和（2）确定PEX作为一种 抗血管生成。 基于细胞的递送系统由细胞组成， 表达包封在中空纤维中的转基因产物， 不同孔隙率的膜装置。 本地交付的眼睛 天然存在的抗血管生成化合物如PEX将 潜在地为PDR提供非破坏性治疗模式。

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.