Targeting the retinoic acid signaling pathway for mitigating visual impairmen in retinal degenerative disorders

摘要 光反应起始于视杆和视锥感光细胞，由视网膜中间神经元处理，并通过突触进行。 传输到视网膜神经节细胞(RGC)，后者以棘波序列的形式将信息发送到大脑。在……里面 退行性视网膜疾病，包括老年性黄斑变性(AMD)和视网膜色素变性 (RP)，光感受器逐渐死亡，剥夺了下游神经元的光敏输入。然而， 最近的证据表明，光感受器的丧失只是这些疾病问题的一部分。下游 视网膜神经元变得过度活跃，视网膜神经节细胞(RGC)在黑暗中自发放电，最高可达 比健康的视网膜快10倍，破坏了视觉信息的正确编码。我们最近报道了 维甲酸(RA)，一种激活基因转录的小分子，是触发RGC的信号 多动症。阻断体内RA受体可以逆转过度活动，揭开光反应的面纱 否则会被自发的RGC发射所遮挡。阻断视网膜中的RA受体也会增加 在RP小鼠模型中学习的视觉行为的对比敏感性。我们在这个项目中的目标是评估 无论是抑制RA信号的药物还是基因疗法都可以改善RP小鼠模型的视力， 希望在患有退行性视网膜疾病的人类中延长有用的视力数年。首先，我们将询问是否 抑制RA信号不仅提高了对光的敏感度，而且实际上还改善了有意识的视觉功能 视力受损的小鼠，用对比敏感度和空间频率阈值的行为测试进行评估。我们 将确定在退变过程中何时RA抑制剂最有效，揭示最佳 开始治疗的时间到了。其次，我们将研究位于视网膜节细胞上游的视网膜神经元，即 双极细胞和无长突细胞。我们将询问这些突触前神经元的病理生理变化 也是由RA信号升高诱导的，以及抑制RAR是否可以逆转这些变化，提供 有效的细胞靶向基因治疗的关键信息。第三，我们将测试视觉是否可以 通过抑制合成RA的酶来改进，使用一种已经得到FDA批准的重新用途的药物 用于其他适应症，为人类临床研究铺平道路。综上所述，该项目将建立 视网膜退行性疾病增加视力的新治疗范例背后的原则证明。

ABSTRACT Light responses are initiated in rod and cone photoreceptors, processed by retinal interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information, in the form of spike trains, to the brain. In degenerative retinal disorders, including Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP), the photoreceptors gradually die off, depriving downstream neurons of light-sensitive input. However, recent evidence suggests that losing photoreceptors is only part of the problem in these disorders. Downstream retinal neurons become hyperactive, with retinal ganglion cells (RGCs) firing spontaneously in darkness at up to 10 times faster than in healthy retina, corrupting the proper encoding of visual information. We recently reported that retinoic acid (RA), a small molecule that activates gene transcription, is the signal that triggers RGC hyperactivity. Blocking the receptor for RA in vivo can reverse hyperactivity, unmasking light responses that would otherwise be obscured by spontaneous RGC firing. Blocking RA receptors in the retina also augments the contrast-sensitivity of learned visual behaviors in a mouse model of RP. Our goal in this project is to assess whether drugs or gene therapies that inhibit RA signaling can improve vision in mouse models of RP, with the hope of extending useful vision for years in humans with degenerative retinal disorders. First, we will ask whether inhibiting RA signaling not only improves light-sensitivity, but actually improves conscious visual function in vision-impaired mice, assessed with behavioral tests of contrast sensitivity and spatial frequency threshold. We will determine how when during the degeneration process RA inhibitors are most effective, revealing the optimal time for beginning treatment. Second, we will investigate retinal neurons that lie upstream of RGCs, namely bipolar cells and amacrine cells. We will ask whether pathophysiological changes in these presynaptic neurons are also induced by elevated RA signaling and whether inhibiting RAR can reverse these changes, providing critical information for effective cellular targeting of gene therapy. Third, we will test whether vision can be improved by inhibiting the enzyme that synthesizes RA, with a re-purposed drug that is already FDA-approved for other indications, paving the way for human clinical studies. Taken together, this project will establish the proof-of-principle behind a new treatment paradigm for augmenting vision in retinal degenerative disorders.