THERAPY FOR DOMINANTLY INHERITED RETINAL DEGENERATIONS

视网膜色素变性(RP)是一组遗传性视网膜变性(RDS)的异质性疾病，全世界每3,500人中就有1人患病。到75岁时，年龄相关性黄斑变性(AMD)影响多达四分之一的人，是美国50岁以上人群失明的主要原因。目前还没有有效的治疗方法来预防RP患者或大多数AMD患者的光感受器退化和视力丧失。研究的方向是在了解这些RDS的发病机制和开发它们的治疗方法之间进行。赞助商的实验室最近证实，视网膜下注射重组腺相关病毒载体持续注射核酶可以延缓RP啮齿动物模型的光感受器丢失，并提高ERG的a波和b波幅度至少3个月。杆状和锥体功能与核酶之间的关系，在很大程度上是未知的。拟议实验的目标是确定单次和多次注射核酶后视锥和视杆感光细胞存活和功能挽救的持续时间，并确定在退化过程中多晚给予核酶可以挽救S334ter和P23H视紫红质突变大鼠的视网膜功能。这些视紫红质基因的突变与在显性遗传的人类RP中发现的相似。我们推测，挽救视杆细胞的存活和功能也将有利于锥体细胞的存活和功能。拟议的研究和培训计划为帮助RP和AMD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RDS疗法的专业知识，对她未来作为一名独立研究人员的职业生涯将非常宝贵。

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.