Chou S-T, Leng Qixin, Mixson A J
Department of Pathology, University of Maryland School of Medicine, MSTF Building, 10 South Pine Street, Baltimore, MD 21201, USA ; Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD 20742.
Drugs Future. 2012 Mar 1;37(3):183-196. doi: 10.1358/dof.2012.037.03.1779022.
Genome editing with the use of zinc finger nucleases has been successfully applied to variety of a eukaryotic cells. Furthermore, the proof of concept for this approach has been extended to diverse animal models from to mice. Engineered zinc finger nucleases are able to target specifically and manipulate disease-causing genes through site-specific double strand DNA breaks followed by non-homologous end joining or homologous recombination mechanisms. Consequently, this technology has considerable flexibility that can result in either a gain or loss of function of the targeted gene. In addition to this flexibility, gene therapy by zinc finger nucleases may enable persistent long term gene modification without continuous transfection- a potential advantage over RNA interference or direct gene inhibitors. With systemic viral delivery systems, this gene-editing approach corrected the mutant factor IX in models of mouse hemophilia. Moreover, phase I clinical trials have been initiated with zinc finger nucleases in patients with glioblastoma and HIV. Thus, this emerging field has significant promise as a therapeutic strategy for human genetic diseases, infectious diseases and oncology. In this article, we will review recent advances and potential risks in zinc finger nuclease gene therapy.
利用锌指核酸酶进行基因组编辑已成功应用于多种真核细胞。此外，这种方法的概念验证已扩展到从[此处原文缺失信息]到小鼠的各种动物模型。工程化锌指核酸酶能够通过位点特异性双链DNA断裂，随后通过非同源末端连接或同源重组机制，特异性地靶向并操纵致病基因。因此，这项技术具有相当大的灵活性，可导致靶向基因功能的获得或丧失。除了这种灵活性之外，锌指核酸酶介导的基因治疗可能能够实现持久的长期基因修饰，而无需持续转染——这是相对于RNA干扰或直接基因抑制剂的一个潜在优势。通过全身病毒递送系统，这种基因编辑方法在小鼠血友病模型中校正了突变的凝血因子IX。此外，针对胶质母细胞瘤和HIV患者的锌指核酸酶I期临床试验已经启动。因此，作为一种针对人类遗传疾病、传染病和肿瘤学的治疗策略，这个新兴领域具有巨大的前景。在本文中，我们将综述锌指核酸酶基因治疗的最新进展和潜在风险。
