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的功能障碍而导致的视觉发色团供应不足对视杆细胞介导的视力具有破坏性影响，并且是人类不可逆失明的主要原因。这种致盲性疾病的早期症状是延迟的视杆细胞介导的暗适应和夜视困难。视觉灵敏度恢复的下降可能是由Rho再生不足引起的，其中无发色团视蛋白的积累组成性地激活信号级联并加速视网膜变性。虽然这种游离视蛋白活性可以被外源性视网膜发色团降低，但当它们的清除有缺陷时，这不能防止有毒类维生素A光产物的积累。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，我们提出了新的视觉色素，与新的发色团类似物再生的视黄基视蛋白，视黄基氯化物对视网膜生理学的影响，在潜在的治疗策略，以保护视网膜的Rho再生受损相关的视网膜退行性疾病的视网膜健康的背景下。首先，我们将在体外研究不同的视黄酰氯异构体的生物化学和功能特性（目的 1），然后在Abca 4-/-Rdh 8-/-小鼠（早发性人Stargardt病模型）和Lrat-/-小鼠（Leber先天性黑蒙（LCA）模型）中测试所选视黄基氯化物的作用（目的2）。最后，我们将评估RBP 4载体增加这些化合物的眼部递送的能力，从而减轻这些小鼠模型中的进行性视网膜变性（目的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).