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，光遗传疗法是一种通过使用分子假体来实现视觉功能的方法，分子假体将信号传输到下游的视觉电路。我们的合作者(和其他人)在动物模型上进行的体外和体内研究表明，光激活的氯泵或通道可以被引入疾病或萎缩性视网膜的特定视网膜细胞类型。在那里，这些分子假体可以实现以前没有的视觉反应。本计划旨在解决与开发光遗传疗法相关的两种不同范式的知识空白和技术限制：1)生理优化形式的卤视紫红质(NpHR)将用于在视杆状感光细胞退化后激活衰竭视锥感光细胞的功能；2)优化通道视紫红质(CHRD)将用于向变性视网膜中的二级视网膜神经元授予光响应。我们将为每个范例设计和开发适当的载体、传递策略和结果衡量标准，开展必要的临床前安全性和有效性研究，并将其中一项研究(NpHR)投入临床试验。在这个过程中，将开发改变腺相关病毒(AAV)转导特性的新策略，设计可应用于人眼的新手术方法，并将定义敏感的、非侵入性的、临床相关的结果指标。在技术发展的同时，我们将评估基因治疗介导的分子假体在人类体内的生物伦理学。这一全面的计划极大地受益于许多有才华的合作者和顾问的智慧和经验，并利用了PI已经为眼部基因治疗翻译研究开发的基础设施。光遗传疗法的成功应用将展示

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 expa