PDF(Pubmed)
Abstract：
Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4-/-) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.
摘要：
黄斑变性与几种重叠疾病有关，包括年龄相关性黄斑变性（AMD）和Stargardt病（STGD）。ATP结合盒亚家族A成员4(ABCA4)中的突变与迟发性干性AMD和早发性STGD相关。此外,两种形式的黄斑变性都表现出视网膜下物质的沉积和光感受器变性。维甲酸相关的孤儿受体α(RORA)调节包括ABCA4、CD59、C3和C5的AMD炎症途径。在这项翻译研究中，我们检查了RORA在减轻Abca4敲除（Abca4-/-）小鼠中的视网膜变性和改善炎症反应方面的功效。AAV5-hRORA处理的小鼠显示沉积物减少，与未治疗的眼睛相比，CD59表达恢复，淀粉样前体蛋白（APP）表达减弱。这种分子拯救与光感受器功能的统计学显著改善相关。这是第一项评估RORA修饰基因疗法对挽救视网膜变性的影响的研究。我们的研究证明了RORA在改善STGD和干性AMD样疾病方面的功效。
