Broad Spectrum Molecular Therapy for Blinding Retina Disorders

治疗致盲性视网膜疾病的广谱分子疗法

• 批准号: 8536302
• 负责人: JEAN BENNETT
• 金额: $ 77.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536302
• 关键词: Address; Animal Model; Atrophic; Bioethics; Characteristics; Chloride Ion; Chlorides; Clinical Trials; Dependovirus; Development; Eye; Halorhodopsins; Human; In Vitro; Knowledge; Light; Mediating; Molecular; Operative Surgical Procedures; Outcome Measure; Process; Prosthesis; Pump; Research Infrastructure; Retina; Retinal; Retinal Cone; Retinal Diseases; Signal Transduction; Translational Research; Vision; Visual; abstracting; cell type; clinically relevant; design; experience; gene therapy; in vivo; novel strategies; optogenetics; preclinical efficacy; preclinical safety; programs; response; retinal neuron; retinal rods; technology development; vector

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

描述 抽象的： 该建议评估了光遗传学疗法的翻译潜力，这种方法通过使用分子假体来实现视觉功能，该方法将其信号传输到下游视觉电路。我们的合作者（和其他）在动物模型中的体外和体内研究表明，可以将光激活的氯化物泵或通道引入患病或萎缩性视网膜中的特定视网膜细胞类型中。在那里，这些分子假体可以允许视觉反应以前没有。本计划旨在解决与两种不同范式中光遗传学疗法发展有关的知识差距和技术局限性：1）生理优化的卤代蛋白（NPHR）形式将用于激活杆光感受器后失败锥光感受体的功能； 2）优化的通道Rhopopsin（CHRD）将用于赋予退化视网膜中二阶视网膜神经元的光反应能力。我们将针对每个范式设计和开发适当的向量，交付策略和结果指标，将进行先决条件的临床前安全和效力研究，并将其中一项研究（NPHR）带入临床试验。在此过程中，将开发改变与腺相关病毒（AAV）的转导特征的新策略，将设计可应用于人眼的新手术方法，并定义敏感，无创，临床相关的结果指标。随着技术的发展，我们将评估基因治疗介导的人类分子假体传递的生物伦理学。这个全面的计划从许多才华横溢的合作者和顾问的智慧和经验中受益匪浅，并利用了PI已经为眼部基因疗法转化研究开发的基础设施。成功应用光遗传疗法将曝光