Photoswitchable channel blockers for treatment of blindness

描述（由申请人提供）：在发达国家，年龄相关性或遗传性视网膜变性导致的光感受器细胞死亡仍然是导致失明的主要原因。在这些疾病中，内视网膜基本上是幸免的。光开关化学物质是一种特殊的药物制剂，其活性可以通过可见光进行调节。我们建议利用这类化合物作为一种方法来逆转失明从视网膜外变性。我们实验室的初步工作已经证明，光开关电压门控钾通道拮抗剂AAQ能够恢复几种外视网膜失明小鼠模型的视网膜电生理反应，并能够恢复失明小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对这两种化合物进行严格的体外和体内测试，以确定哪一种化合物可以进入临床开发；对其在体外对灵长类动物视网膜的影响进行了深入分析

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.