Photoswitchable channel blockers for treatment of blindness

用于治疗失明的光开关通道阻断剂

基本信息

批准号：
8608067
负责人：
Russell N. Van Gelder
金额：
$ 145.45万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：由年龄相关或遗传性视网膜变性引起的感光细胞死亡仍然是发达国家失明的主要原因。内层视网膜在很大程度上不会受到这些疾病的影响。光开关化学品是特定的药物制剂，其活性可以使用可见光进行调节。我们建议利用此类化合物作为逆转外视网膜变性失明的方法。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能够恢复几种外层视网膜失明小鼠模型的电生理视网膜反应，并且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 显示出改善的光谱响应、动力学和眼睛耐受性。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体外和体内严格测试，以确定将哪一种化合物推进临床开发；提出深入分析它们对体外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功效测试，目的是申请新药申请，以便在本次拨款结束时进行人体临床研究。