Novel Therapy for Wet Age-Related Macular Degeneration

湿性年龄相关性黄斑变性的新疗法

• 批准号: 6736617
• 负责人: SHEILA CONNELLY
• 金额: $ 22.32万
• 依托单位: ADVANCED VISION THERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736617
• 关键词: Lentivirus; angiogenesis inhibitors; biotechnology; fluorescein angiography; gene delivery system; gene expression; gene therapy; genetically modified animals; laboratory mouse; macular degeneration; plasmids; retina circulation; therapy design /development; transfection /expression vector; western blottings

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.

描述（由申请人提供）：湿性年龄相关性黄斑变性（AMD）是发达国家失明的主要原因，也是一种医疗需求未得到满足的疾病。与湿性 AMD 相关的失明是由新生血管形成引起的，治疗的目的是抑制这种进展。 Advanced Vision Therapies, Inc. (AVT) 的战略是将其基因传递系统与新型有效的抗血管生成转基因相结合，以快速开发和销售治疗湿性 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 是一种不会引起人类疾病的牛慢病毒。 AVT 将 BIV 载体系统与新型抗血管生成转基因 T2-TrpRS 相结合，并在相关的啮齿动物眼新生血管模型中评估该系统。第一阶段项目有三个具体目标。 1）。 T2-TrpRS 表达盒的生成和体外表征。 T2-TrpRS 是 Trp tRNA 合成酶的蛋白水解切割片段，通常不从细胞中分泌。因此，将产生几个包含替代信号序列的表达盒，并评估转染至人类后的有效分泌 细胞。 2) BIV-T2-TrpRS载体的产生和生产。使用最好的 T2-TrpRS 根据特定目标 1 的表达盒，将制备 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 表达。 3）。在眼新生血管相关啮齿动物模型中评估 T2-TrpRS 载体功效。在特定目标 2 中生成和表征的载体将在视网膜下注射到小鼠视网膜新生血管模型中后进行功效评估。新血管形成/血管渗漏的抑制将通过多种方法进行评估，包括荧光素血管造影和组织学分析。 II 期研究将侧重于积累足够的数据以保证 AVT 载体的临床开发。