Non-hydrolysable analogs of retinal chromophore; potential new therapeutics to prevent retinal degeneration

 描述(由申请人提供)：由于参与其再生的关键蛋白质功能障碍，视觉生色团的供应不足，对视杆介导的视力具有毁灭性的影响，并构成人类不可逆性失明的主要原因。这种致盲疾病的早期症状是视杆细胞介导的暗适应延迟和夜视困难。视觉敏感度恢复的下降可能是由于Rho再生不足，无生色团的视蛋白积累，结构性地激活了信号级联，加速了视网膜的退化。虽然这种游离视蛋白活性可以通过外源性视网膜发色团减少，但这不能防止有毒的类维A酸类光产物的积累，因为它们的清除是有缺陷的。因此，迫切需要一种替代的治疗方法来对抗这种情况下的视力丧失。在这里，我们建议在潜在的治疗策略的背景下，研究新的视觉色素、用新的发色团类似物再生的视黄酰视蛋白、视黄醇氯化物对视网膜生理学的影响，以保护与Rho再生受损相关的视网膜退行性疾病的视网膜健康。首先，我们将在体外研究不同的视黄酰氯异构体的生化和功能性质(目的 1)，然后在ABCA4-/-Rdh8-/-小鼠(早发性人类Stargardt病模型)和Lrat-/-小鼠(Leber先天性黑色素(LCA)模型)上测试选定的视黄酰氯的效果(目标2)。最后，我们将评估RBP4载体增加这些化合物的眼部递送的能力，从而缓解这些小鼠模型中的进行性视网膜退化(目标3)。

 DESCRIPTION (provided by applicant): An insufficient supply of visual chromophore due to dysfunction of key proteins involved in its regeneration has devastating effects on rod-mediated vision, and comprises a leading cause of irreversible blindness in humans. Early signs of such blinding diseases are delayed rod cell-mediated dark adaptation and difficulty with night vision. The decline in recovery of visual sensitivity is likely caused by inadequate Rho regeneration with accumulation of chromophore-free opsin that constitutively activates the signaling cascade and accelerates retinal degeneration. Although such free opsin activity can be reduced by exogenous retinal chromophore, this fails to prevent the buildup of toxic retinoid photo-products when their clearance is defective. Thus, an alternative therapeutic approach is urgently needed for combating vision loss under such conditions. Here we propose to investigate the effects of new visual pigments, retinyl-opsins regenerated with novel chromophore analogs, retinyl chlorides on retina physiology in context of potential therapeutic strategy to protect retinal healh in retinal degenerative diseases associated with compromised Rho regeneration. First, we will study the biochemical and functional properties of different retinyl chloride isomers in vitro (Aim 1), and then test the effects of selected retinyl chlorides in both Abca4-/-Rdh8-/- mice, a model of early onset human Stargardt disease and in Lrat-/- mice, a model of Leber congenital amaurosis (LCA) (Aim 2). Finally, we will assess the capability of the RBP4 carrier to increase the ocular delivery of these compounds, and thereby alleviate progressive retinal degeneration in these mouse models (Aim 3).