THERAPY FOR DOMINANTLY INHERITED RETINAL DEGENERATIONS

视网膜色素变性（RP）是一组异质性遗传性视网膜变性（RD），影响全球3,500人中的1人。年龄相关性黄斑变性（AMD）影响多达四分之一的75岁的人，并且是美国50岁以上人群失明的主要原因。目前没有有效的治疗方法来预防RP患者或大多数AMD患者的感光细胞变性和视力丧失。研究工作正朝着了解这些RD的发病机制和开发治疗方法的方向发展。申办方的实验室最近证明，视网膜下注射重组腺相关病毒载体用于在RP啮齿动物模型中持续注射核酶可延迟感光细胞丧失并升高ERG中的a波和b波振幅至少3个月。核酶在视杆细胞和视锥细胞功能之间的关系，在很大程度上是未知的。提出的实验的目的是确定锥和杆感光细胞的生存和功能救援的持续时间，通过单次和多次给药的核酶，并确定如何晚在变性过程中核酶管理可以挽救视网膜功能的S334 ter和P23 H视紫红质突变大鼠系。视紫红质基因中的这些突变与显性遗传的人RP中发现的突变相似。我们推测，视杆细胞的存活和功能的拯救也将有利于视锥细胞的存活和功能。拟议的研究和培训计划为RP和AMD患者提供了巨大的机会。候选人将获得使用RD动物模型开发和提供RD疗法的专业知识，这对她未来作为独立研究人员的职业生涯非常有价值。

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.