Using light-sensitive channels to restore vision for blinding retinal diseases

描述（由申请人提供）：视网膜退行性疾病中感光细胞的严重丧失可能导致部分或完全失明。目前，一旦光感受器丢失，没有有效的治疗方法可以恢复失去的视力。我们正在探索一种新的策略，将对光不敏感的第二或第三级视网膜神经元遗传转化为光敏细胞，从而赋予缺乏光感受器的视网膜光敏感性。概念验证研究已经证明了通道视紫红质-2（ChR 2）和盐视紫红质（HaloR）在内视网膜神经元中的功能性表达的可行性，并导致具有视网膜变性的小鼠模型的视网膜中的开和关光响应的恢复。本提案的目的是继续在啮齿动物模型中进行原理验证研究，以解决对开发临床应用治疗策略至关重要的问题。具体而言，我们将研究HaloR在体内视网膜神经元中的长期表达，并研究ChR 2和HaloR介导的视网膜神经元光反应的潜在机制。我们还将探索ChR 2和HaloR对视网膜内神经元和/或视网膜神经节细胞的亚细胞区室的特定群体的靶向表达。此外，我们将研究ChR 2和HaloR介导的光响应特性，从正常和视网膜变性小鼠的靶细胞及其下游神经元。我们的长期目标是开发一种治疗或治愈视网膜变性引起的失明的新策略。拟议的研究将提供将这种新的治疗策略推向临床应用所需的动物模型的关键知识。这些研究还将推进我们对正常和疾病条件下视网膜回路和功能的了解，并为基础视网膜研究开发新的工具。 公共卫生相关性：我们的目标是开发一种治疗或治愈视网膜变性引起的失明的新策略。如果成功，这种策略可能用于治疗或治愈所有由感光细胞丧失引起的常见失明。

DESCRIPTION (provided by applicant): The severe loss of photoreceptor cells in retinal degenerative diseases could result in partial or complete blindness. Currently, once the photoreceptors are lost, there is no effective treatment available for restoring lost vision. We are exploring a novel strategy of genetically converting light-insensitive second- or third-order retinal neurons into photosensitive cells, thus imparting light-sensitivity to retinas that lack photoreceptors. Proof-of-concept studies have demonstrated the feasibility of the functional expression of channelrhodopsin-2 (ChR2) and halorhodopsin (HaloR) in inner retinal neurons and resulting restoration of ON and OFF light responses in the retina of a mouse model with retinal degeneration. The objective of this proposal will continue the proof-of-principle studies in rodent models to address issues that are important for developing this treatment strategy for clinical applications. Specifically, we will study the long-term expression of HaloR in inner retinal neurons in vivo and investigate the underlying mechanism(s) of ChR2 and HaloR-mediated light responses in retinal neurons. We will also explore targeted expression of ChR2 and HaloR to specific population(s) of inner retinal neurons and/or sub cellular compartments of retinal ganglion cells. Furthermore, we will investigate the ChR2 and HaloR-mediated light response properties from the targeted cells and their downstream neurons in normal and retinal degenerative mice. Our long-term goal is to develop a novel strategy for treating or curing blindness caused by retinal degeneration. The proposed studies will provide critical knowledge in animal models required for advancing this new treatment strategy to clinical applications. The studies will also advance our knowledge of retinal circuitry and functions under normal and diseased conditions as well as develop new tools for basic retinal research. PUBLIC HEALTH RELEVANCE: Our goal is to develop a novel strategy for treating or curing blindness caused by retinal degeneration. If successful, this strategy could be potentially used to treat or cure all common blindness caused by photoreceptor loss.