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: 8711469
• 负责人: JEAN BENNETT
• 金额: $ 80万
• 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/8711469
• 关键词: Address; American; Animal Model; Atrophic; Bioethics; Blinded; Blindness; Characteristics; Chloride Ion; Chlorides; Clinical Trials; Dependovirus; Development; Diabetic Retinopathy; Disease; Epidemic; Eye; Halorhodopsins; Human; In Vitro; Individual; Inherited; Knowledge; Lead; Light; Location; Macular degeneration; Mediating; Molecular; Nature; Operative Surgical Procedures; Outcome Measure; Process; Property; Prosthesis; Pump; Quality of life; Rare Diseases; Reagent; Research; Research Infrastructure; Retina; Retinal; Retinal Cone; Retinal Detachment; Retinal Diseases; Retinitis Pigmentosa; Retinopathy of Prematurity; Safety; Signal Transduction; Translational Research; Vision; Visual; Visually Impaired Persons; abstracting; blind; cell type; clinically relevant; combat; design; effective therapy; experience; gene therapy; in vivo; injured; novel; 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 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.

描述 抽象的： 该提案评估了光遗传学疗法的翻译潜力，这种方法是可视化的 通过使用将其信号传输到下游的分子假体来实现功能 视觉电路。我们的合作者（和其他人）在动物模型中的体外和体内研究 证明可以将光活化的氯化物泵或通道引入特定的视网膜细胞 患病或萎缩性视网膜类型。在那里，这些分子假体可以允许视觉反应 以前的地方没有。本计划旨在解决知识差距和技术 与两种不同范式的光遗传学疗法有关的局限性：1）生理学上 优化形式的卤淡蛋白（NPHR）将用于激活失败的锥形光感受器的功能 杆光感受器退化后； 2）优化的ChannelRhopopsins（CHRD）将用于 在退化的视网膜中赋予对二阶视网膜神经元的光反应能力。我们将设计和 为每个范式制定适当的向量，交付策略和结果指标 排除先决条件的临床前安全和效力研究，并将其中一项研究（NPHR）带到 临床试验。在此过程中，改变腺相关的转导特征的新策略 将开发病毒（AAV），可以应用于人眼的新外科手术方法将是 将定义设计，敏感，无创，临床相关的结果指标。同时 随着技术的开发，我们将评估基因治疗介导的介导的生物伦理学 人类的分子假体。这个全面的计划从智慧和 许多才华横溢的合作者和顾问的经验，并利用了基础设施 PI已经为眼部基因治疗转化研究开发。成功应用 光遗传学疗法将扩大基因可能可以治疗的疾病靶标数量 急剧治疗。它将从分离的领域改变视网膜基因治疗靶标的数量 本质上流行病的孤儿疾病。此外，试剂，策略和 该项目中开发的技术进步将对许多其他眼部和区域外有用 申请。最后，这个项目的结果不仅可以导致大幅改善 数百万个人的生活质量，但他们也可以为发展新基因的发展铺平道路 治疗其他毁灭性感官疾病的治疗方法。