Ambient light activatable opsin based therapy for age-related macular degeneration

 描述（由申请人提供）：由于年龄相关性黄斑变性（AMD）而发生严重的视力丧失，美国约有1100万人患有某种形式的AMD，预计到2050年将翻一番。目前大多数临床治疗主要集中在减缓疾病的进展，因为除了视网膜假体之外，既没有可以阻止变性的治疗方法，也没有可以恢复由于变性而丧失的视力的治疗方法。然而，目前的系统受到分辨率差（更高的电极密度需要更多的电流，导致产热）、一段时间内的视网膜损伤和由于手术植入引起的细胞过度生长的限制。使用视网膜细胞的光遗传敏化具有优于电刺激的几个优点，例如单细胞分辨率、细胞特异性和最小侵入性。然而，光遗传学使能的视力恢复的临床转化由于单个视蛋白的窄光谱灵敏度而遭受由具有比环境光高的强度数量级的蓝色光源的主动刺激的缺点。为了允许基于环境光的刺激，我们提出利用（经由玻璃体内注射）携带多色视蛋白的慢病毒载体（VMCO）来使光变性AMD视网膜中的视网膜神经节细胞对不同颜色的光敏感，从而允许宽光谱兴奋性并因此对环境光具有显著更高的敏感性。本SBIR第I阶段的总体目标 该项目的目的是证明在晚期AMD小鼠模型中，通过VMCO致敏的视网膜神经节细胞（RGC）的环境水平白光刺激，视觉的行为恢复。为了这个目标，我们有以下目的：（i）评价病毒递送的多色视蛋白敏化的AMD小鼠模型的变性视网膜的长期存活力和功能;和（ii）在变性视网膜的多色视蛋白敏化后，晚期AMD小鼠模型中视觉的行为恢复。这项提案是NanoScope Technologies、Retina Foundation以及德克萨斯大学Mohanty博士和Kim博士的实验室之间的合作成果。该提议的成功将导致通过常规玻璃体内注射携带视蛋白构建体的病毒来治疗患有AMD的患者的新的临床方法。我们相信，这种治疗将导致恢复高分辨率的视力在AMD患者的白光刺激的多色视蛋白敏感的RGC在环境光水平。在完成第一阶段后，我们设想了第二阶段SBIR，目标是（i）优化最终产品设计和方法，（ii）确定AMD人群的治疗，（iii）向FDA提交孤儿药许可申请，以及（iv）为产品和方法的商业化提供核心营销材料。

 DESCRIPTION (provided by applicant): Severe loss of vision occurs due to age-related macular degeneration (AMD) and approximately 11 million people in the US have some form of AMD which is expected to double by 2050. Most of the current clinical treatments are primarily focused on slowing down the progression of the disease, as there is neither a cure that can stop the degeneration nor a therapy, other than retinal prostheses, that can restore vision lost due to the degeneration. Current systems, however, are limited by poor resolution (higher electrode density requiring more current, leading to heat production), retinal damage over a time period and cellular overgrowth due to surgical implantation. Use of optogenetic sensitization of retinal cells has several advantages over electrical stimulation such as single-cell resolution, cellular specificity and minimal-invasiveness. However, clinical translation of optogenetic enabled vision restoration suffers from the drawback of active stimulation by blue light source having intensity order of magnitude higher than ambient light owing to the narrow spectral sensitivity of single opsins. To allow ambient-light based stimulation, we propose to utilize (via intravitreal injection lenti-viral vector carrying multi- color opsins (VMCO) to sensitize retinal ganglion cells in photodegenerated AMD retina to different colors of light, allowing broad spectral excitability and thus, significantly higher sensitivity to ambient light. The overall objective of this Phase I SBIR project is to demonstrate behavioral restoration of vision in mice models of late-stage AMD with ambient-level white-light stimulation of retinal ganglion cells (RGCs), sensitized by VMCO. Towards this goal we have following aims: (i) Evaluation of long-term viability and functioning of virally-delivered multi-color opsin sensitized degenerated-retina of AMD mice model; and (ii) Behavioral restoration of vision in mice models of late stage AMD after multi-color opsin sensitization of the degenerated-retina. This proposal is a collaborative effort between NanoScope Technologies, Retina Foundation, and Drs. Mohanty and Kim's laboratories at University of Texas. Success of this proposal will lead to a new clinical approach for treating patients with AMD by conventional intravitreal injection of virus carrying opsin constructs. We believe that such treatment will lead to restoration of high-resolution vision in AMD patients by white-light stimulation of multi-color opsin sensitized RGCs at ambient light level. Upon completion of the Phase I we envision a Phase II SBIR targeted at (i) optimizing the final product design and method, (ii) identifying AMD-population for treatment, (iii) submission of orphan drug license application to FDA, and (iv) providing core marketing material for commercializing the product and method.