Scheie Eye Institute, University of Pennsylvania, 51 North 39th St, Philadelphia, PA 19104, USA.
Prog Retin Eye Res. 2010 Sep;29(5):398-427. doi: 10.1016/j.preteyeres.2010.04.002. Epub 2010 Apr 24.
Leber congenital amaurosis (LCA) is a rare hereditary retinal degeneration caused by mutations in more than a dozen genes. RPE65, one of these mutated genes, is highly expressed in the retinal pigment epithelium where it encodes the retinoid isomerase enzyme essential for the production of chromophore which forms the visual pigment in rod and cone photoreceptors of the retina. Congenital loss of chromophore production due to RPE65-deficiency together with progressive photoreceptor degeneration cause severe and progressive loss of vision. RPE65-associated LCA recently gained recognition outside of specialty ophthalmic circles due to early success achieved by three clinical trials of gene therapy using recombinant adeno-associated virus (AAV) vectors. The trials were built on multitude of basic, pre-clinical and clinical research defining the pathophysiology of the disease in human subjects and animal models, and demonstrating the proof-of-concept of gene (augmentation) therapy. Substantial gains in visual function of clinical trial participants provided evidence for physiologically relevant biological activity resulting from a newly introduced gene. This article reviews the current knowledge on retinal degeneration and visual dysfunction in animal models and human patients with RPE65 disease, and examines the consequences of gene therapy in terms of improvement of vision reported.
Leber 先天性黑矇（LCA）是一种罕见的遗传性视网膜变性，由十多个基因突变引起。这些突变基因中的 RPE65 高度表达在视网膜色素上皮中，它编码的视黄醇异构酶对于产生形成视网膜中视杆和视锥感光细胞中的视觉色素的生色团至关重要。由于 RPE65 缺陷导致的先天性生色团产生损失以及进行性光感受器变性导致严重和进行性视力丧失。由于使用重组腺相关病毒 (AAV) 载体的三项基因治疗临床试验取得了早期成功，RPE65 相关的 LCA 最近在眼科专业圈子之外得到了认可。这些试验建立在大量的基础、临床前和临床研究之上，这些研究定义了人类和动物模型中疾病的病理生理学，并证明了基因（增强）治疗的概念验证。临床试验参与者的视觉功能的显著提高为新引入的基因产生的具有生理相关性的生物学活性提供了证据。本文综述了 RPE65 疾病的动物模型和人类患者的视网膜变性和视觉功能障碍的现有知识，并根据报告的视力改善情况检查了基因治疗的后果。
