Engineering Novel AAV Vectors for Retinal Gene Therapy

用于视网膜基因治疗的新型 AAV 载体工程

• 批准号: 7149417
• 负责人: DAVID V SCHAFFER
• 金额: $ 21.69万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149417
• 关键词: birth; cell type; directed evolution; disease /disorder model; gene therapy; genes; retina

DESCRIPTION (provided by applicant): Gene therapy has vast potential for treating and potentially curing a wide variety of disorders, in particular in a number of retinal diseases including glaucoma, age-related macular degeneration, and photoreceptor diseases. However, gene delivery technologies require significant improvements in cellular targeting, efficiency, and safety before promising findings in animal studies can be translated to the clinic. In particular, for retinal gene therapy it would be highly advantageous to transduce a single cell type that spans the entire retina for the delivery and secretion of a general neuroprotective factor throughout the retina to protect numerous populations of neurons that are affected by different retinal diseases, from retinal ganglion cells to photoreceptors. In addition, ideally this single cell type should be accessible from an intravitreal injection, as subretinal injections are more invasive and disruptive to the retina. Unfortunately, there is no vector capable of efficiently infecting the cell type that meets these needs, Muller glia. Vectors based on adeno-associated virus (AAV) have proven themselves to be highly promising in numerous retinal disease models, but they are also unfortunately incapable of Muller cell infection. We have developed novel directed evolution technology to generate new mutants of AAV with new properties, including altered receptor binding, and we propose to evolve variants capable of efficient Muller cell transduction. In parallel, the basic mechanisms of AAV transduction of Muller cells will be explored. Finally, results will be translated to photoreceptor disease model. The novel approaches developed in this work will have general impact for the molecular engineering of enhanced viral gene delivery vehicles for a number of retinal diseases.

描述（由申请人提供）：基因治疗具有治疗和潜在治疗多种疾病的巨大潜力，尤其是在包括青光眼，与年龄相关的黄斑变性和感光疾病在内的许多视网膜疾病中。然而，基因递送技术需要在动物研究中有希望的发现之前，需要显着改善细胞靶向，效率和安全性，可以将其转化为诊所。特别是，对于视网膜基因治疗，将单个细胞类型转导跨整个视网膜的单个细胞类型将是有利的，以在整个视网膜中递送和分泌一般的神经保护因子，以保护许多受视网膜神经节细胞影响不同的视网膜疾病影响的神经元种群，从视网膜神经节细胞到光感受器。此外，理想情况下，应从玻璃体内注射中获取这种单细胞类型，因为视网膜下注射更具侵入性和对视网膜的破坏性。不幸的是，没有能够有效感染满足这些需求的细胞类型的载体。基于腺相关病毒（AAV）的载体证明了自己在许多视网膜疾病模型中非常有前途，但不幸的是，它们也无法感染Muller细胞感染。我们已经开发了新型的定向进化技术，以生成具有新特性的AAV的新突变体，包括改变受体结合，我们建议进化能够有效的Muller细胞转导的变体。同时，将探索Muller细胞AAV转导的基本机制。最后，结果将转化为感光疾病模型。这项工作中开发的新方法将对许多视网膜疾病增强的病毒基因输送车的分子工程产生一般影响。