Photoswitchable channel blockers for treatment of blindness

描述(申请人提供)：由年龄相关性或遗传性视网膜变性引起的光感受器细胞死亡仍然是发达国家失明的主要原因。在这些疾病中，视网膜内部在很大程度上是安全的。光开关化学物质是一种特殊的药理物质，其活性可以通过可见光来调节。我们建议利用这类化合物作为一种方法来逆转视网膜外部变性所致的失明。我们实验室的初步工作表明，光开关电压门控钾通道拮抗剂AAQ能够恢复几种视网膜外盲模型小鼠的视网膜电生理反应，并能够恢复盲鼠的瞳孔光反应和对光的行为反应。然而，AAQ在波长敏感性、动力学和潜在毒性方面存在局限性。两种“第二代”光开关化合物，DENAQ和PhENAQ，在眼睛中表现出更好的光谱响应、动力学和耐受性。我们建议在小鼠、大鼠、狗和灵长类动物模型中严格测试这两种化合物在体外和体内的相互作用，以确定将哪种化合物应用于临床开发；建议在体外深入分析它们对灵长类视网膜的影响，以便 了解它们拯救人类失明的潜力；并建议进行所需的临床前毒理学和疗效测试，目的是申请新药申请，以便在这笔赠款结束时进行人类临床研究。

DESCRIPTION (provided by applicant): Photoreceptor cell death from age-related or hereditary retinal degeneration remains the leading cause of blindness in the developed world. The inner retina is largely spared in these diseases. Photoswitch chemicals are specific pharmacologic agents whose activity can be modulated using visible light. We propose utilizing this class of compounds as an approach to reverse blindness from outer retinal degeneration. Preliminary work from our laboratories has demonstrated that the photoswitchable voltage gated potassium channel antagonist AAQ is able to restore electrophysiological retinal responses to several mouse models of outer retinal blindness, and is able to restore pupillary light responses and behavioral responses to light in blind mice. However, AAQ has limitations in terms of its wavelength sensitivity, kinetics, and potential toxicity. Two 'second generation' photoswitch compounds, DENAQ and PhENAQ, show improved spectral response, kinetics, and tolerance in the eye. We propose rigorously testing these two compounds against each other in vitro and in in vivo in mouse, rat, dog, and primate models to determine which to take forward into clinical development; propose an in depth analysis of their effects on the primate retina in vitro, in order to understand their potential for rescue of human blindness; and propose performing required preclinical toxicology and efficacy tests with the goal of applying for a new drug application to allow human clinical studies at the conclusion of this grant.