Early-onset retinal degenerations

描述(申请人提供)：早发性视网膜退行性疾病， 包括那些被称为Leber先天性黑素症的人，是一种严重的 没有治疗就失明了。视网膜色素上皮(RPE)的突变 编码RPE65的基因是导致这些失明的为数不多的已知分子原因之一 疾病。该应用程序的目的是调查潜在的口腔 RPE65相关性人视网膜变性动物模型的治疗 确定具有分子相似视网膜的患者的候选资格 疾病。有一个好处是，一只转基因小鼠 “小动物”模型和自然产生的犬“大动物”模型分别是 可用。在初步研究中，视网膜血流和视网膜生理学 对RPE65基因缺陷小鼠进行了分析，发现没有杆状光色素和 严重损害了杆状生理。有一种明显的疾病表型 光感受器功能严重异常，在形态接近 很正常。光感受器和RPE的缓慢退化导致 疾病后期的结构和功能损害。使用 口服顺式维甲酸，试图绕过生化反应 由遗传异常引起的视觉(类视黄醇)循环中的阻塞。 在48小时内，有杆状感光色素的形成和戏剧性 杆状生理学的改进。当前的具体目标 这些令人鼓舞的结果直接导致了多学科的应用： (1)确定RPE65缺陷小鼠的短期和长期后果 口服顺式维甲酸；(2)研究RPE65突变犬的疾病模型 机制和对口服顺式维甲酸的反应；以及(3)定义疾病 RPE65基因在早发性视网膜变性患者中的表达 突变，特别是询问是否像模型一样，存在 当光感受器功能几乎不存在但视网膜时的可检测阶段 结构仍然存在，因此是进行有效干预的机会 不依赖于战略。这个应用程序提供了一个路线图，希望 将在未来得到很好的旅行，因为我们目前正在寻求恢复视力 从分子原因确定不可治愈的遗传性视网膜变性 在人类失明的情况下，以实验和试验为基础的机制 干预小动物和大动物模型，然后绕回一圈 受折磨的人类澄清与他们的相关性和他们对特定 治疗，长期目标是安全有效的临床试验。

DESCRIPTION (provided by applicant): Early-onset retinal degenerative diseases, including those termed Leber congenital amaurosis, are a severe form of blindness without treatment. Mutations in the retinal pigment epithelium (RPE) gene encoding RPE65 are one of the few known molecular causes of these blinding diseases. The objective of this application is to investigate a potential oral therapy in animal models of RPE65-associated human retinal degeneration and determine the candidacy of patients with the molecularly comparable retinal disease. There is the advantage that both a genetically engineered murine "small animal" model and a naturally occurring canine "large animal" model are available. In preliminary studies, retinoid flow and retinal physiology in Rpe65-deficient mice were analyzed and there was no rod photo pigment and severely impaired rod physiology. There is a distinct disease phenotype with photoreceptor function severely abnormal at a time when morphology is nearly normal. Slow degeneration of photoreceptors and RPE causes a convergence of structural and functional damage at later disease stages. Using an orally-administered cis-retinoid, an attempt was made to bypass the biochemical blockade in the visual (retinoid) cycle caused by the genetic abnormality. Within 48 hours, there was formation of rod photopigment and dramatic improvement in rod physiology. The specific aims of the current multi-disciplinary application lead directly from these encouraging results: (1) determine in Rpe65-deficient mice the short- and long-term consequences of oral cis-retinoids; (2) study the RPE65-mutant canine model for disease mechanism and response to oral cis-retinoids; and (3) define the disease expression in humans with early-onset retinal degenerations due to RPE65 mutations, specifically inquiring whether, like the models, there is a detectable phase when photoreceptor function is nearly absent but retinal structure remains, and thereby an opportunity for effective intervention independent of strategy. This application provides a route map that hopefully will be well-traveled in the future as we seek to restore vision in currently incurable genetic retinal degenerations from identification of molecular cause in human blindness, to experimentation and trials of mechanism-based intervention in small and large animal models, and then a circling back to the afflicted humans to clarify relevance to them and their candidacy for specific treatments, with the long-term goal of safe and efficacious clinical trials.