THERAPY FOR DOMINANTLY INHERITED RETINAL DEGENERATIONS

显性遗传性视网膜变性的治疗

• 批准号: 6792214
• 负责人: JACQUE LYNNE DUNCAN
• 金额: $ 14.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792214
• 关键词: cell transplantation; cone cell; electroretinography; gene mutation; genetically modified animals; injection /infusion; laboratory rat; macular degeneration; nonhuman therapy evaluation; polymerase chain reaction; retina degeneration; retinitis pigmentosa; ribosomes; rod cell; visual photoreceptor

Retinitis pigmentosa (RP) is a heterogeneous group of hereditary retinal degenerations (RDs) that affects 1 in 3,500 people worldwide. Age- related macular degeneration (AMD) affects as many as 1 in 4 people by the age of 75 and is the leading cause of blindness in people over age 50 in the US. There are currently no effective treatments to prevent photoreceptor degeneration and vision loss in patients with RP, or in most patients with AMD. Research efforts are being directed toward between understanding of the pathogenesis of these RDs and to develop therapies for them. The Sponsor's laboratory has recently demonstrated that subretinal injection of recombinant adeno-associated virus vectors for sustained injection of ribozymes in a rodent model of RP can delay photoreceptor loss and elevate a- and b-wave amplitudes in the ERG for at least 3 months. The relationship between rod and cone function with ribozymes, is largely unknown. The goals of the proposed experiments are to determine the duration of cone and rod photoreceptor survival and functional rescue by single and multiple administrations of ribozymes and to determine how late in the degenerative process ribozyme administration can rescue retinal function in S334ter and P23H rhodopsin mutant rat lines. These mutations in the rhodopsin gene are similar to those found in dominantly inherited human RP. We hypothesize that rescue of rod cell survival and function will also benefit cone cell survival and function. The proposed research and training plan provides enormous opportunities to help patients with both RP and AMD. The expertise the Candidate will gain using animal models of RD to develop and deliver therapies for RDs will be extremely valuable in her future career as an independent researcher.

色素性视网膜炎（RP）是一组异质的遗传性视网膜变性（RDS），影响了全球3500人中的1人。到75岁时，与年龄相关的黄斑变性（AMD）影响了多达四分之一的人，是美国50岁以上人失明的主要原因。目前尚无有效的治疗方法可预防RP患者或大多数AMD患者的感光变性和视力丧失。研究工作是针对对这些RD发病机理的理解，并为其开发疗法。发起人的实验室最近表明，在RP的啮齿动物模型中，重组腺相关病毒载体的重组下注入核酶持续注射会延迟感光受体损失，并至少在ERG中升高A-和B波振幅至少3个月。杆和锥功能与核酶之间的关系在很大程度上是未知的。提出的实验的目标是确定核酶的单个和多个施用锥形和杆光感受器的存活以及功能拯救的持续时间，并确定退化过程中的核酶给药可以挽救S334Ter和p23h Rhopopsin突变大鼠的核酶施用如何挽救视网膜功能。视紫红质基因中的这些突变与主要遗传的人RP中发现的突变相似。我们假设拯救杆细胞存活和功能也将使锥细胞的存活和功能有益。拟议的研究和培训计划为帮助RP和AMD的患者提供了巨大的机会。候选人将使用RD动物模型来开发和提供RD的疗法的专业知识将在她作为独立研究人员的未来职业中非常有价值。