Gene therapy for Leber congenital amaurosis: advances and future directions.
Gene therapy for Leber congenital amaurosis: advances and future directions.
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DOI：
10.1007/s00417-012-2028-2
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Sisk RA
中科院分区：
文献类型：
--
作者：
Hufnagel RB;Ahmed ZM;Corrêa ZM;Sisk RA
莱伯先天性黑朦（LCA）是一种先天性视网膜营养不良，在早期导致严重的视力丧失。对LCA患者的基因突变和表型相关性的综合分析使得对光感受器变性和功能障碍的分子途径的理解有了显著的改善。本文旨在综述视网膜基因治疗LCA的相关文献，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1996-2011年的同行评审和索引出版物进行文献检索。关键词包括“利伯氏先天性黑朦”、LCA、RPE65、“锥杆营养不良”、“基因治疗”和各种组合的“人体试验”。1996年以前的开创性文章是从原始来源和最初搜索的评论中选择的。文章的选择是基于针对性的临床，遗传，和治疗的主题审查在这个手稿。LCA患者的眼底照片是回顾性地从作者之一（R.A.S）的临床实践中获得的。在此，我们回顾了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的未来方向。Theodor Leber对LCA的原始描述和随后的研究表明，这种疾病具有早发性失明的严重性。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质产物。动物模型提供了一种方法来测试新的治疗策略，即基因治疗。基于这些实验，三个独立的临床试验测试了RPE65基因突变患者视网膜下传递病毒基因治疗的安全性。最近，功效研究取得了令人鼓舞的结果。最初的安全性研究表明，视网膜下传递具有亚临床免疫或手术后遗症的病毒载体有希望的结果。总的来说，这些初步研究表明，病毒载体基因治疗的结果是非常有希望的，安全有效的。未来的研究测量光感受器功能的潜在改善可能依赖于视网膜成像和电生理测试的最新进展。
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.
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影响因子：
4.2
作者：
Cideciyan, Artur V.;Hauswirth, William W.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.
RPE65的慢病毒基因转移在Leber先天性amurosis小鼠模型中挽救了锥体的生存和功能。
影响因子：
15.8
作者：
Bemelmans, Alexis-Pierre;Kostic, Corinne;Crippa, Sylvain V.;Hauswirth, William W.;Lem, Janis;Munier, Francis L.;Seeliger, Mathias W.;Wenzel, Andreas;Arsenijevic, Yvan
通讯作者：
Arsenijevic, Yvan
影响因子：
15.9
作者：
Ashtari, Manzar;Cyckowski, Laura L.;Bennett, Jean
通讯作者：
Bennett, Jean
影响因子：
3.5
作者：
Barker, Susie E.;Broderick, Cathryn A.;Robbie, Scott J.;Duran, Yanai;Natkunarajah, Mythili;Buch, Prateek;Balaggan, Kamaljit S.;MacLaren, Robert E.;Bainbridge, James W. B.;Smith, Alexander J.;Ali, Robin R.
通讯作者：
Ali, Robin R.
影响因子：
3.4
作者：
Birch, DG;Peters, AY;Travis, GH
通讯作者：
Travis, GH