Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity.
Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity.
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DOI：
10.1007/s11684-011-0159-1
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发表时间：
2011-12
影响因子：
8.1
通讯作者：
Dunbar, Cynthia E
中科院分区：
文献类型：
--
作者：
Wu, Chuanfeng;Dunbar, Cynthia E
基于病毒的载体被广泛用于造血干细胞（HSC）基因治疗，并且具有永久整合到基因组DNA中的能力，从而驱动校正基因在所有造血谱系中的长期表达。迄今为止，HSC基因治疗已成功地应用于临床，用于改善少数患有X连锁严重联合免疫缺陷（SCID-X1）、腺苷脱氨酶缺乏症（ADA-SCID）、肾上腺脑白质营养不良（ALD）、地中海贫血、慢性肉芽肿病（CGD）和Wiskott-Aldrich综合征（WAS）的患者的临床结果。然而，在这些HSC基因治疗临床试验中的一些期间观察到不良事件，其与通过整合的前病毒载体插入激活原癌基因相关，导致克隆扩增和最终发展为白血病。已经进行了大量的研究，以了解载体介导的遗传毒性的分子基础，目的是开发更安全的载体和低风险的基因治疗方案。本文将总结目前的信息造血干细胞和祖细胞的插入突变的机制，由于整合基因转移载体，讨论现有的检测方法预测遗传毒性和定位载体整合位点，并介绍新开发的方法，以尽量减少遗传毒性的一种方式，进一步推动HSC基因治疗的临床应用。
Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the ability to integrate permanently into genomic DNA, thus driving long-term expression of corrective genes in all hematopoietic lineages. To date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy (ALD), thalassemia, chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS). However, adverse events were observed during some of these HSC gene therapy clinical trials, linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity, with the aim of developing safer vectors and lower-risk gene therapy protocols. This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors, discuss the available assays for predicting genotoxicity and mapping vector integration sites, and introduce newly-developed approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.