基因治疗：肝豆状核变性治愈的新希望

摘要/Abstract

摘要： 肝豆状核变性（hepatolenticular degeneration，HLD）又叫威尔逊病（Wilson disease，WD），是一种ATP7B基因突变导致的常染色体隐性遗传病，以铜离子代谢障碍为主要特征，发病年龄较广。由于ATP7B基因突变，ATP7B蛋白功能障碍，进入肝脏的铜离子不能合成铜蓝蛋白，亦不能通过胆汁进行排泄，有毒的铜离子异常沉积在肝脏、肾脏、脑、眼等多个部位，导致组织器官损伤和疾病表现，严重危害患者健康。 WD一经确诊需终身治疗，现有疗法包括低铜饮食、药物治疗、手术治疗等，但均存在对依从性要求高、疗效有限、有不良反应等问题，因此WD患者的医疗需求远未被满足。作为一种遗传性代谢性疾病，从病因入手，采用基因治疗的方式可从根本上纠正ATP7B基因异常状态。根据对载体的理解和已有研究，腺病毒(AdV)、慢病毒(LV)等载体存在表达时间短或插入毒性风险等问题，不适用于WD治疗。近年来，腺相关病毒(AAV)载体由于安全性好、免疫原性低、转导效率高、表达时间长等特点逐渐成为基因治疗的理想载体。本研究通过重点介绍ATP7B基因突变导致的铜代谢障碍疾病，陈述现有治疗方式的利弊，对一些在研的新方法和疾病治愈的可能性进行综合分析，简要总结疾病特点、致病机制、诊疗现状等，并分析目前基因治疗获得的结果与进展，对基因治疗用于WD治疗的必要性、科学性、及其前景进行理性的分析与展望。

关键词: font-size:medium, ">肝豆状核变性；基因治疗；病毒载体；腺相关病毒

Abstract: Hepatolenticular degeneration (HLD)， also known as Wilson disease (WD)， is an autosomal recessive genetic disease caused by ATP7B gene mutation， mainly characterized by copper ion metabolism disorders. Due to ATP7B gene mutation and the resulting ATP7B protein dysfunction， copper ions cannot synthesize ceruloplasmin， nor can they be excreted through bile in the liver， resulting in abnormal deposition of toxic copper ions in liver， kidney， brain， eyes and other parts of the body， leading to tissue and organ damage and disease manifestations and serious harm to the health of pationts. WD requires lifelong treatment once diagnosed. Existing methods of treatment include low-copper diet， drug therapy， surgical treatment， etc.， which have the problems such as high compliance requirements， limited efficacy， or side effects. As a result， the medical needs of WD are far from being met. As a hereditary metabolic disease， the best choice of treatment is fundamentally correcting the abnormal state of ATP7B genebygene therapy. According to the understanding of vectors and previous studies， adenovirus， lentivirus have some problems such as short expression time or insertion toxicity risk， which are not suitable for WD treatment. In recent years， adeno-associated virus vector(AAV) was found to be an ideal vector for gene therapy due to its good safety， low immunogenicity， high transfer efficiency and long expression time. This study focuses on copper metabolism disorders caused by ATP7B gene mutation， states the advantages and disadvantages of existing treatment methods， and makes a comprehensive analysis of some new methods under research and the possibility of disease cure，briefly summarize the characteristics， pathogenic mechanism， diagnosis and treatment status of WD， analyze the current results and progress of gene therapy， and rationally analyze the necessity， scientificity and prospect of gene therapy for WD treatment.

Key words: Hepatolenticular degeneration, Gene therapy, Virus vectors, Adeno-associated virus(AAV)

中图分类号:

R742.4

夏艳, 吴小兵. 基因治疗：肝豆状核变性治愈的新希望[J]. 中国医药导刊, 2023, 25(11): 1085-1091.

XIA Yan, WU Xiaobing. Gene Therapy： the New Hope for the Cure of Hepatolenticular Degeneration[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2023, 25(11): 1085-1091.

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