Early-onset retinal degenerations

早发性视网膜变性

• 批准号: 6317116
• 负责人: SAMUEL GREGORY JACOBSON
• 金额: $ 62.24万
• 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/6317116
• 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）：早发性视网膜变性疾病， 包括那些被称为利伯先天性黑蒙，是一种严重的形式， 失明而不治疗。视网膜色素上皮（RPE）突变 编码RPE 65的基因是这些致盲的少数已知分子原因之一 疾病本申请的目的是研究一种潜在的口腔 RPE 65相关的人视网膜变性的动物模型中的治疗， 确定具有分子上可比的视网膜病变的患者的候选资格， 疾病有一个优点，即基因工程鼠， “小动物”模型和天然存在的犬“大动物”模型， available.在初步研究中， 分析RPE 65缺陷小鼠，没有视杆细胞光色素， 严重损害了视杆细胞的生理机能有一种独特的疾病表型， 感光细胞功能严重异常的时候，形态接近 正常光感受器和RPE的缓慢退化会导致视网膜色素上皮细胞的会聚 结构和功能的损害在后期疾病阶段。使用 口服顺式维甲酸，试图绕过生化 由遗传异常引起的视觉（类维生素A）周期阻滞。 在48小时内，有杆色素和戏剧性的形成， 杆生理学改善。当前的具体目标 多学科应用直接源于这些令人鼓舞的结果： (1)在Rpe 65缺陷小鼠中确定 口服顺式维甲酸;（2）研究RPE 65突变犬疾病模型 机制和对口服顺式维甲酸的反应;和（3）定义疾病 在患有RPE所致早发性视网膜变性的人中的表达65 突变，特别是询问是否，像模型一样， 当感光器功能几乎不存在但视网膜 结构仍然存在，因此有机会进行有效干预 独立于战略。这个应用程序提供了一个路线图， 在我们目前寻求恢复视力的过程中， 无法治愈的遗传性视网膜变性的分子原因鉴定 在人类失明的情况下， 在小型和大型动物模型中进行干预，然后回到 折磨人类，以澄清与他们的相关性和他们的候选人的具体 治疗，长期目标是安全有效的临床试验。