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，是一种巨大的未满足医疗需求的疾病。与湿性AMD相关的失明是由新生血管引起的，治疗旨在抑制这一进展。先进视觉疗法公司（AVT）的策略是将其基因传递系统与一种新型有效的抗血管生成转基因相结合，以快速开发和销售一种针对湿性AMD的优越产品。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，这是一种不会引起人类疾病的牛慢病毒。AVT将结合BIV载体系统和一种新型抗血管生成转基因t2 - trpr，并在相关的啮齿动物眼部新生血管模型中对该系统进行评估。这个第一阶段的项目有三个具体目标。1）. T2-TrpRS表达盒的生成及体外表征。t2 - trpr是Trp tRNA合成酶的蛋白水解裂解片段，通常不从细胞分泌。因此，将产生几个包含替代信号序列的表达盒，并评估转染到人体内后的有效分泌

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.