Novel Therapy for Wet Age-Related Macular Degeneration

描述（由申请人提供）：湿性年龄相关性黄斑变性（AMD）是发达国家致盲的主要原因，是一种医疗需求严重不足的疾病。与湿性AMD相关的失明是由新血管形成引起的，治疗旨在抑制这种进展。Advanced Vision Therapies，Inc. (AVT)该公司的战略是将其基因传递系统与一种新的、有效的抗血管生成转基因相结合，以快速开发和销售一种治疗湿性AMD的上级产品。AVT开发了一种基于牛免疫缺陷病毒（BIV）的最先进的基因传递系统，BIV是一种不会引起人类疾病的牛慢病毒。AVT将联合收割机将BIV载体系统与新型抗血管生成转基因T2-TrpRS相结合，并在眼部新生血管的相关啮齿动物模型中评估该系统。第一阶段项目有三个具体目标。1）。T2-TrpRS表达盒的产生和体外表征。T2-TrpRS是Trp tRNA合成酶的蛋白水解切割片段，并且通常不从细胞分泌。因此，将产生几种表达盒，其含有替代信号序列，并在转染到人细胞中后评估其有效分泌。 细胞2)BIV-T2-TrpRS载体的生成和生产。使用最佳T2-TrpRS 为了获得来自特异性目标1的T2-TrpRS表达盒，将制备BIV载体，按比例放大用于体内研究，并在载体转导人细胞后评价T2-TrpRS表达。3）。在眼部新生血管形成的相关啮齿动物模型中评估T2-TrpRS载体功效。将在视网膜下注射到视网膜新生血管形成的小鼠模型中后，评价在特定目标2中生成和表征的载体的功效。将通过几种方法（包括荧光素血管造影和组织学分析）评价对新生血管形成/血管渗漏的抑制。II期研究将集中于积累足够的数据，以保证AVT载体的临床开发。

DESCRIPTION (provided by applicant): Wet age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and represents a disease with a great unmet medical need. The blindness associated with wet AMD is caused by neovascularization and treatments are aimed at inhibiting this progress. The Advanced Vision Therapies, Inc. (AVT) strategy is to combine its gene delivery system with a novel and potent anti-angiogenic transgene to rapidly develop and market a superior product for wet AMD. AVT developed a state-of-the-art gene delivery system based on the bovine immunodeficiency virus (BIV), a bovine lentivirus that does not cause human disease. AVT will combine the BIV vector system with a novel anti-angiogenic transgene, T2-TrpRS, and evaluate this system in relevant rodent models of ocular neovascularization. There are three specific aims for this Phase I project. 1). Generation and in vitro characterization of T2-TrpRS expression cassettes. T2-TrpRS is a proteolytic cleavage fragment of the Trp tRNA synthetase, and is not normally secreted from cells. Therefore, several expression cassettes will be generated, containing alternative signal sequences, and evaluated for efficient secretion following transfection into human cells. 2) Generation and production of a BIV-T2-TrpRS vector. Using the best T2-TrpRS expression cassette from Specific Aim 1, a BIV vector will be made, scaled up for in vivo studies, and evaluated for T2-TrpRS expression following vector transduction of human cells. 3). Evaluation of the T2-TrpRS vector efficacy in a relevant rodent model of ocular neovascularization. The vector generated and characterized in Specific Aim 2 will be evaluated for efficacy following subretinal injection into a mouse model of retinal neovascularization. Inhibition of neovascularization/vascular leakage will be evaluated through several methods including fluorescein angiography and histological analyses. Phase II studies will focus on accruing sufficient data to warrant clinical development of the AVT vector.