Chromophore Effects in Genetically Diverse Forms of Retinal Dystrophy

描述（由申请人提供）：视网膜退行性疾病是造成毁灭性视力障碍的原因，影响了全世界数百万人。发病年龄相对较早的单基因疾病已被定位到200多个遗传位点。维生素A视觉周期突变的发现为针对视网膜变性（RD）的特定遗传原因的治疗方法的首次成功临床试验开辟了道路。在类视黄醇异构酶基因RPE65突变的个体中，使用增加视网膜发色团11-顺式视网膜（11cRAL）水平的基因治疗方法获得了令人信服的结果。然而，这种策略目前仅限于治疗导致视觉周期功能丧失的突变。因此，迫切需要找到治疗其他RD基因型的方法。我们的兴趣是确定扩大使用发色团来治疗遗传多样性RD的可行性。尽管在某些情况下，发色团水平的增加与光损伤和脂褐素积累的风险增加有关，但充分认识11cRAL在视网膜中的复杂作用是很重要的。11cRAL不仅对启动视觉反应至关重要，而且还作为稳定视觉色素结构所需的强大伴侣。11cRAL产生或可用性的缺陷阻碍了视紫红质和视锥蛋白的折叠、运输和稳定性，从而导致细胞程序性死亡，尤其是影响视锥细胞。这种深刻的依赖性表明，增加发色团可能有助于治疗由一系列原发性缺陷引起的相关RD表型。我们的提议的具体目的是验证一个假设，即发色团水平的增加可以减少由影响视觉色素功能、视觉循环效率和光感受器膜微环境的突变引起的人类RD大鼠和小鼠模型的疾病表型。我们的实验将涉及通过全身递送类视黄醇和视网膜下注射病毒载体来增加发色团水平，在研究中将比较可能或不可能对治疗有反应的表型的体内结果。我们的研究结果将为目前可用的技术在治疗范围更广的RD基因型方面的有效性提供关键的见解，从而在不久的将来为更多受影响的个体提供治疗的可能性。

DESCRIPTION (provided by applicant): Degenerative diseases of the retina are responsible for devastating visual handicap affecting millions of individuals worldwide. Monogenic disorders with relatively early age-of-onset have been mapped to over 200 genetic loci. The discovery of mutations in the vitamin A visual cycle opened a path to the first successful clinical trials of therapies targeted to a specific genetic cause of retinal degeneration (RD). In individuals with mutations in the retinoid isomerase gene RPE65, compelling outcomes were obtained using gene therapy approaches that increase retina levels of the chromophore 11-cis retinal (11cRAL). However, such strategies are currently limited to the treatment of mutations resulting in visual cycle loss-of-function. Thus, there is an urgent need to find treatments for additional RD genotypes. Our interest is to determine the feasibility of expanding the use of chromophore supplementation for the treatment of genetically diverse forms of RD. Although in some circumstances increased levels of chromophore are associated with increased risk of light damage and lipofuscin accumulation, it is important to fully recognize the complex role of 11cRAL in the retina. 11cRAL is essential not only for initiating the visual response, but also serves as a powerful chaperone needed to stabilize the structures of the visual pigments. Deficits in 11cRAL production or availability impede the folding, trafficking and stability of rhodopsin and cone opsins, thereby contributing to programmed cell death, particularly affecting the cone cells. This profound dependence suggests that increasing chromophore may be useful for treating relevant RD phenotypes caused by a range of primary defects. The specific aims of our proposal will test the hypothesis that increase in chromophore levels can diminish the disease phenotype of rat and mouse models of human RD caused by mutations affecting visual pigment function, visual cycle efficiency, and the photoreceptor membrane microenvironment. Our experiments will involve increasing chromophore levels by systemic delivery of retinoid, and by subretinal injection of viral vectors, in studies that will compare in vivo outcomes in phenotypes that are likely, or unlikely, to respond to treatment. The results of our study will provide critical insight into the effectiveness of currently available technologies for treating an expanded range of RD genotypes, and thus the possibilities for offering therapy to greater numbers of affected individuals in the near future. PUBLIC HEALTH RELEVANCE: The vitamin A analog 11cRAL is essential for maintaining the function and viability of the rod and cone photoreceptor cells. Strategies that supplement 11cRAL levels in the retina have proven effective for treating certain forms of inherited retinal degeneration caused by mutations in genes necessary for 11cRAL synthesis. Our interest is to obtain the supporting data needed to apply this strategy more broadly to the treatment of genetically diverse forms of retinal degeneration, with the long-term goal of increasing the number of patients who may benefit from this approach.