Pharmacological studies of rhodopsin metabolism

摘要：暗光视觉色素视紫红质(RHO)的基因突变会导致视网膜色素变性(RP)， 这种遗传性视网膜变性目前还没有有效的药物治疗方法。我们的长期合作 目的是确定导致RP中光感受器死亡的分子事件，并开发有效的 针对这些事件的小分子药物，以保护视网膜结构和视觉功能。Rho蛋白 错误折叠导致视杆细胞死亡。我们的中心假设是：稳定Rho结构的小分子， 或者那些导致错误折叠的Rho降解的药物可以减轻Rho相关的ADRP。我们最近发现了两个 新颖而有效的先导化合物：1)YC-001，一种Rho的非视网膜伴侣，拯救多个 导致RP的Rho突变错误；以及2)美国食品和药物管理局(FDA)批准的一种药物 在体外诱导错误折叠的Rho降解，并具有强大的抗炎活性。使用 通过对Rho P23H基因敲入小鼠模型的研究，我们将确定Rho P23H对RP的疗效、作用机制和 这两种化合物首先在视网膜组织块培养中的安全性，然后在体内进行玻璃体内注射 注射YC-001以受控药物释放配方或通过玻璃体腔间歇注射 FDA批准的药物的最佳间隔时间。我们将利用最先进的视网膜成像技术和 电生理学技术评估视网膜结构和视觉功能。我们将进行生化 和转录组分析，以确定调节视紫红质稳态的药物靶向途径。这个 这项研究的结果将提供这两种先导化合物在 AdRP的啮齿动物模型，从中我们将建立一个清晰的分子网络连接视紫红质的表达， 折叠、降解和视网膜炎症与视网膜变性的进展有关，我们将评估 这些化合物作为潜在的治疗RP的疗效。

Summary: Genetic mutations of the dim-light visual pigment, rhodopsin (Rho), cause retinitis pigmentosa (RP), and no effective pharmacological treatment is available for this inherited retinal degeneration. Our long-term goal is to determine the molecular events that contribute to photoreceptor death in RP and develop effective small molecule drugs targeting these events that preserve the retinal structure and visual function. Rho protein misfolding causes rod cell death in RP. Our central hypothesis is: small molecules that stabilize Rho structure, or those induce degradation of misfolded Rho can mitigate Rho-associated adRP. We recently discovered two novel and potent lead compounds: 1) YC-001, a non-retinal chaperone of Rho that rescues folding of multiple misfolded Rho mutants that cause RP; and 2) a U.S. Food and Drug Administration (FDA)-approved drug that induces misfolded Rho degradation in vitro, and that possesses potent anti-inflammatory activity. Using the well-studied Rho P23H knock-in mouse model of RP, we will determine the efficacy, mechanism of action, and safety of these two compounds firstly in the isolated retinae explant culture, and then in vivo by an intravitreal injection of YC-001 encapsulated in a controlled drug release formula, or via intermittent intravitreal injections of the FDA-approved drug with optimized intervals. We will utilize state-of-the-art retinal imaging and electrophysiology techniques to evaluate the retinal structure and visual function. We will conduct biochemical and transcriptome analyses to identify the drug targeting pathways that regulate rhodopsin homeostasis. The results from this study will provide comprehensive pharmacological profiles of the two lead compounds in a rodent model of adRP, from which we will build a clear molecular network connecting rhodopsin expression, folding, degradation and retinal inflammation with the progression of retinal degeneration and we will assess the efficacy of these compounds as potential treatments for RP.