Broad Spectrum Molecular Therapy for Blinding Retina Disorders

描述 摘要： 这项建议评估了光遗传疗法的翻译潜力，这是一种视觉疗法 功能是通过使用分子假体来实现的，分子假体将其信号传输到下游 视觉回路。我们的合作者(和其他人)在体外和活体动物模型上的研究已经 证明了光激活的氯泵或通道可以被引入特定的视网膜细胞 视网膜病变或萎缩的类型。在那里，这些分子假体可以实现视觉反应 以前，那里什么都没有。本方案旨在解决知识差距和技术问题 光遗传疗法在两种不同范式下发展的局限性：1)生理学 优化形式的卤视紫红质(NpHR)将用于激活衰竭的视锥体光感受器的功能 在杆状感光细胞退化后；2)优化的通道视紫红质将用于 使退化视网膜中的二级视网膜神经元具有光反应性。我们将设计和 为每个范例制定适当的载体、交付战略和成果衡量标准 进行必备的临床前安全性和有效性研究，并将其中一项研究(NpHR)带到 临床试验。在这个过程中，改变腺相关蛋白转导特性的新策略 病毒(AAV)将被开发，可以应用于人眼的新手术方法将被开发 将定义设计的、敏感的、非侵入性的、与临床相关的结果衡量标准。同时进行 随着技术的发展，我们将评估基因治疗介导的 人类的分子假体。这一全面的计划极大地受益于智慧和 拥有众多才华横溢的合作者和顾问的经验，并利用 PI已经开发出用于眼部基因治疗的转译研究。成功地应用了 光遗传疗法将扩大潜在可用基因治疗的疾病靶点的数量 戏剧性的治疗。它将改变视网膜基因治疗靶点的数量，从孤立的领域 从孤儿疾病到自然界流行的疾病。此外，试剂、策略和 该项目开发的技术进步将对许多其他眼科和眼外科有用。 申请。最后，这个项目的结果不仅可以显著改善 数百万人的生活质量，但他们也可以为新基因的开发铺平道路 治疗其他破坏性感觉神经疾病的治疗方法。

DESCRIPTION Abstract: This proposal evaluates the translational potential of optogenetic therapy, an approach whereby visual function is achieved through the use of a molecular prosthesis that transmits its signals to downstream visual circuits. Studies in vitro and in vivo in animal models by our collaborators (and others) have demonstrated that light-activated chloride pumps or channels can be introduced into specific retinal cell types in diseased or atrophic retinas. There, these molecular prostheses can permit visual responses where before, there were none. The present program aims to address the knowledge gaps and technical limitations relevant to development of optogenetic therapy in two different paradigms: 1) Physiologically optimized forms of Halorhodopsin (NpHR) will be used to activate function of failing cone photoreceptors after the rod photoreceptors have degenerated; 2) Optimized Channelrhodopsins (ChRd) will be used to confer light responsiveness to second order retinal neurons in degenerated retinas. We will design and develop the appropriate vectors, delivery strategies and outcome measures for each paradigm, will carry out the prerequisite preclinical safety and efficacy studies, and will bring one of the studies (NpHR) to clinical trial. In the process, novel strategies of altering the transduction characteristics of adeno-associated virus (AAV) will be developed, new surgical approaches which could be applied to human eyes will be devised, and sensitive, noninvasive, clinically relevant outcome measures will be defined. Simultaneous with development of the technology, we will evaluate the bioethics of gene therapy-mediated delivery of molecular prostheses in humans. This comprehensive program benefits greatly from the wisdom and experience of many talented collaborators and advisors and takes advantage of the infrastructure that the PI has already developed for ocular gene therapy translational research. Successful application of optogenetic therapy will expand the number of disease targets that are potentially treatable by gene therapy dramatically. It will change the number of retinal gene therapy targets from the realm of isolated orphan diseases to conditions that are epidemic in nature. In addition, the reagents, strategies and technical advances developed in this project will be useful for many other ocular and extra-ocular applications. Finally, not only could the results from this project lead to a significant improvement in the quality of life for millions of individuals, but they could also pave the way for development of novel gene therapy approaches for the treatment of other devastating sensorineural diseases.