Early-onset retinal degenerations

早发性视网膜变性

• 批准号: 6635725
• 负责人: SAMUEL GREGORY JACOBSON
• 金额: $ 33.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635725
• 关键词: clinical research; disease /disorder onset; dogs; electrophysiology; gene expression; gene mutation; genetic disorder; human subject; human therapy evaluation; laboratory mouse; molecular pathology; nonhuman therapy evaluation; oral administration; pathologic process; retina degeneration; retinal pigment epithelium; retinoids; visual photoreceptor; vitamin therapy

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.

描述（由申请人提供）：早发性视网膜退行性疾病， 包括那些被称为莱伯先天性黑蒙的人，是一种严重的形式 未经治疗失明。视网膜色素上皮 (RPE) 突变 编码 RPE65 的基因是导致这些致盲的少数已知分子原因之一 疾病。该应用程序的目的是调查潜在的口服 RPE65相关人类视网膜变性动物模型的治疗 确定具有分子可比视网膜的患者的候选资格 疾病。基因工程小鼠的优点是 “小动物”模型和自然发生的犬类“大型动物”模型是 可用的。在初步研究中，类维生素A流动和视网膜生理学 对 Rpe65 缺陷小鼠进行分析，发现没有视杆细胞色素和 视杆生理机能严重受损。具有明显的疾病表型 当形态接近时，光感受器功能严重异常 普通的。光感受器和 RPE 的缓慢退化导致 疾病后期的结构和功能损伤。使用 口服顺式维A酸，试图绕过生化 由遗传异常引起的视觉（类维生素A）循环受阻。 48小时内，形成棒状感光色素并产生戏剧性的效果。 杆生理学的改善。当前的具体目标 多学科应用直接源自这些令人鼓舞的结果： (1) 确定 Rpe65 缺陷小鼠的短期和长期后果 口服顺式维A酸； (2)研究RPE65突变犬疾病模型 口服顺式维A酸的机制和反应； (3) 定义疾病 RPE65 在患有早发性视网膜变性的人类中表达 突变，特别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的可检测阶段 结构仍然存在，因此有机会进行有效干预 独立于策略。该应用程序提供了一个路线图，希望能够 当我们目前寻求恢复视力时，将来会经常旅行 分子病因鉴定无法治愈的遗传性视网膜变性 在人类的盲目性中，对基于机制的实验和试验 对小型和大型动物模型的干预，然后又回到了 受苦的人类澄清与他们的相关性以及他们对特定目标的候选资格 治疗，以安全有效的临床试验为长期目标。