Novel Therapy for Wet Age-Related Macular Degeneration

描述(申请人提供)：湿性老年性黄斑变性(AMD)是发达国家导致失明的主要原因，代表着一种巨大的未得到满足的医疗需求。与湿性AMD相关的失明是由新生血管引起的，治疗的目的是抑制这一进展。先进视觉疗法公司(AVT)的战略是将其基因递送系统与一种新颖而有效的抗血管生成转基因相结合，以迅速开发和销售一种治疗湿性AMD的优质产品。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是一种不会导致人类疾病的牛慢病毒。AVT将把BIV载体系统与一种新型的抗血管生成转基因T2-TrpRS结合起来，并在相关的眼部新生血管啮齿动物模型中对该系统进行评估。这一阶段的项目有三个具体目标。1)。T2-TrpRS表达框的制备及体外鉴定。T2-TrpRS是Trp tRNA合成酶的蛋白水解性切割片段，通常不从细胞中分泌。因此，将产生几个包含可供选择的信号序列的表达盒，并评估其在导入人类后的有效分泌 细胞。2)BIV-T2-TrpRS载体的构建和生产。使用最佳T2-TrpRS 来自特定目的1的表达盒将被制作成BIV载体，放大用于体内研究，并在载体转导人类细胞后评估T2-TrpRS的表达。3)。T2-TrpRS载体在相关眼部新生血管啮齿动物模型中的疗效评估。在特定目标2中产生和表征的载体将在视网膜下注射到视网膜新生血管的小鼠模型中后进行疗效评估。对新生血管/血管渗漏的抑制将通过几种方法进行评估，包括荧光素血管造影术和组织学分析。第二阶段的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.