Department of Pediatrics, Division of Pediatric Ophthalmology, University of Cincinnati and Cincinnati Children's Hospital, College of Medicine, 3333 Burnet Ave, ML 7003, Cincinnati, OH 45229, USA.
Graefes Arch Clin Exp Ophthalmol. 2012 Aug;250(8):1117-28. doi: 10.1007/s00417-012-2028-2. Epub 2012 May 29.
Leber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.
A literature search of peer-reviewed and indexed publications from 1996-2011 using the PubMed search engine was performed. Key terms included "Leber congenital amaurosis", LCA, RPE65, "cone-rod dystrophy", "gene therapy", and "human trials" in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).
Herein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.
Initial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.
Leber 先天性黑矇（LCA）是一种先天性视网膜营养不良，会导致患者在早期出现严重的视力丧失。对 LCA 患者的基因突变和表型相关性进行综合分析，使得人们对光感受器退化和功能障碍的分子途径有了更深入的了解。本文旨在回顾有关 LCA 视网膜基因治疗的文献，包括历史描述、临床前动物研究和人体临床试验。
使用 PubMed 搜索引擎对 1996 年至 2011 年的同行评议和索引出版物进行文献检索。关键词包括“Leber 先天性黑矇”、LCA、RPE65、“锥-杆营养不良”、“基因治疗”和“人体试验”，以各种组合形式出现。1996 年以前的主要文献从最初的检索中选择了原始资料和综述。本文根据与临床、遗传和治疗主题的相关性选择了文章。从作者之一（R.A.S.）的临床实践中回顾性地获得了 LCA 患者的眼底照片。
本文回顾了 LCA 作为一种遗传性疾病的文献、迄今为止人类基因治疗试验的结果以及在遗传水平上治疗遗传性视网膜疾病的可能未来方向。Theodor Leber 对 LCA 的最初描述以及随后的研究表明，这种疾病的严重性在于其早期失明。致病遗传突变的发现揭示了参与光感受器发育和视觉转导的基因和蛋白产物。动物模型为测试新的治疗策略（即基因治疗）提供了一种手段。这些实验产生了三项独立的临床试验，测试了将病毒基因治疗递送至 RPE65 基因突变患者的视网膜下的安全性。最近，进行了疗效研究，结果令人鼓舞。
最初的安全性研究表明，视网膜下递送至病毒载体具有亚临床免疫或手术后遗症的良好结果。总体而言，这些初步研究表明，病毒载体基因治疗的结果非常有前景、安全且有效。未来衡量潜在改善光感受器功能的研究可能依赖于最近在视网膜成像和电生理测试方面的进展。
