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：
8916750
负责人：
Russell N. Van Gelder
金额：
$ 97.95万
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）：与年龄相关或遗传性视网膜变性导致的感光细胞死亡仍然是发达国家失明的主要原因。内部视网膜在这些疾病中基本上幸免。 Photoswitch化学物质是特定的药理学剂，可以使用可见光调节活性。我们建议利用这类化合物作为逆转视网膜变性的一种方法。我们实验室的初步工作表明，可拍照的电压玻璃通道通道拮抗剂AAQ能够恢复对几种视网膜外视力的小鼠模型的电生理视网膜响应，并且能够恢复盲小鼠光中光的瞳孔光反应和行为反应。但是，AAQ在其波长敏感性，动力学和潜在毒性方面存在局限性。两种“第二代”的Photoswitch化合物Denaq和Phenaq在眼睛中显示出改进的光谱响应，动力学和耐受性。我们建议在体外和体内彼此严格测试这两种化合物在小鼠，大鼠，狗和灵长类动物模型中，以确定哪些是临床发育的；对其对灵长类动物视网膜在体外的影响进行深入分析，了解他们拯救人类失明的潜力；并提出执行所需的临床前毒理学和功效测试，目的是申请新药物应用，以允许在该赠款结束时进行人类临床研究。