摘要
威斯科特-奥尔德里奇二氏综合征(WAS):一种单基因X连锁原发性免疫缺陷症,也表现为血小板减少、湿疹和对肿瘤及自身免疫性疾病的易感性。除非能成功移植HLA匹配的造血干细胞(HSC),否则WAS患者的寿命将大幅缩短。然而,一些WAS患者缺乏匹配的捐献者,并且不少造血干细胞移植的患者患有自身免疫性疾病等并发症。通过基因改良的自体造血干细胞治疗,作为一种新的治疗方法,可能适用于所有WAS患者。为了达到这个目的,我们使用初始γ 逆转录病毒载体(RV)建立了几种WAS的基因治疗方法,并随后培育出了HIV的慢病毒载体( LV)。本文首先介绍了在WAS 小鼠模型上进行的临床前研究的结果,然后讨论了RV和LV-转导的HSC不同的阶段的I / II期临床试验结果。两种基因治疗方法都会导致康复的WASP表达,相关的功能缺陷和临床改善。而RV介导的基因治疗与白血病的高发有关,但是,我们用基于LV的HSC基因疗法治疗了第一位患者,并根据得到的结果,得到了一条安全的风险 - 收益曲线。
关键词: 基因疗法、慢病毒载体、原发性免疫缺陷、威斯科特-奥尔德里奇二氏综合征
Current Gene Therapy
Title:Gene Therapy for Wiskott-Aldrich Syndrome
Volume: 14 Issue: 6
Author(s): Marita Bosticardo, Francesca Ferrua, Marina Cavazzana and Alessandro Aiuti
Affiliation:
关键词: 基因疗法、慢病毒载体、原发性免疫缺陷、威斯科特-奥尔德里奇二氏综合征
摘要: The Wiskott-Aldrich Syndrome (WAS) is a monogenic X-linked primary immunodeficiency characterised also by thrombocytopenia, eczema, and a high susceptibility to develop tumours and autoimmunity. WAS patients have a severely reduced life expectancy, unless they undergo a successful HLA-matched haematopoietic stem cell (HSC) transplantation. However, several WAS patients lack a compatible donor and complications, such as autoimmunity, can arise in a significant fraction of HSC transplanted patients. Administration of WAS gene-corrected autologous HSC represents an alternative therapeutic approach, potentially applicable to all WAS patients. To this aim, several gene therapy approaches for WAS using initially γ-retroviral vectors (RVs) and subsequently HIV-based lentiviral vectors (LVs) have been developed. In the present review, we will first describe the results of the preclinical studies conducted in the murine model of WAS and then discuss the outcome of different phase I/II clinical trials using RV or LV- transduced HSC. Both gene therapy approaches led to restored WASP expression, correction of functional defects and clinical improvement. While RV-mediated gene therapy was associated with a high occurrence of leukaemia, results obtained in the first patients treated with LV-based HSC gene therapy indicate a safer risk-benefit profile.
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Bosticardo Marita, Ferrua Francesca, Cavazzana Marina and Aiuti Alessandro, Gene Therapy for Wiskott-Aldrich Syndrome, Current Gene Therapy 2014; 14 (6) . https://dx.doi.org/10.2174/1566523214666140918103731
DOI https://dx.doi.org/10.2174/1566523214666140918103731 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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