Genotoxicity of retroviral hematopoietic stem cell gene therapy.
Genotoxicity of retroviral hematopoietic stem cell gene therapy.
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DOI：
10.1517/14712598.2011.562496
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发表时间：
2011-05
影响因子：
4.6
通讯作者：
Trobridge GD
中科院分区：
文献类型：
--
作者：
Trobridge GD
逆转录病毒载体已被开发用于造血干细胞(HSC)的基因治疗，并已成功治愈了X连锁严重联合免疫缺陷(SCID-X1)、腺苷脱氨酶缺陷(ADA-SCID)、肾上腺脑白质营养不良和Wiskott-Aldrich综合征。然而，在HSC基因治疗的临床试验中，整合载体前病毒介导的遗传毒性导致了克隆扩增，在某些情况下甚至导致了白血病。为了开发更安全的载体和更安全的基因治疗方案，人们已经进行了大量研究，以了解载体介导的遗传毒性的分子基础。这些遗传毒性研究是推进HSC基因治疗的关键。本文就逆转录病毒载体的遗传毒性机制作一综述。它还包括在过去20年中在设计更安全的基因治疗载体以及临床试验和大型动物模型中整合位点分析方面的进展。介绍了逆转录病毒介导的遗传毒性机制，以及在HSC基因治疗中导致克隆性扩张和白血病的危险因素。对病毒-宿主相互作用和下一代载体的持续研究将进一步提高未来HSC基因治疗载体和方案的安全性。
Retroviral vectors have been developed for hematopoietic stem cell (HSC) gene therapy and have successfully cured X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy, and Wiskott-Aldrich syndrome. However, in HSC gene therapy clinical trials, genotoxicity mediated by integrated vector proviruses has led to clonal expansion, and in some cases frank leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity with the aim of developing safer vectors and safer gene therapy protocols. These genotoxicity studies are critical to advancing HSC gene therapy. This review provides an introduction to the mechanisms of retroviral vector genotoxicity. It also covers advances over the last 20 years in designing safer gene therapy vectors, and in integration site analysis in clinical trials and large animal models. Mechanisms of retroviral-mediated genotoxicity, and the risk factors that contribute to clonal expansion and leukemia in HSC gene therapy are introduced. Continued research on virus–host interactions and next-generation vectors should further improve the safety of future HSC gene therapy vectors and protocols.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.2
作者：
Aker, Mari;Tubb, Julie;Emery, David W.
通讯作者：
Emery, David W.
影响因子：
3.7
作者：
Arumugam, Paritha I.;Urbinati, Fabrizia;Malik, Punam
通讯作者：
Malik, Punam
根据靶细胞的基因表达和染色质构象，基因治疗患者中逆转录病毒载体的整合特征是细胞特异性的。
影响因子：
11.1
作者：
Biasco, Luca;Ambrosi, Alessandro;Pellin, Danilo;Bartholomae, Cynthia;Brigida, Immacolata;Roncarolo, Maria Grazia;Di Serio, Clelia;von Kalle, Christof;Schmidt, Manfred;Aiuti, Alessandro
通讯作者：
Aiuti, Alessandro
影响因子：
20.3
作者：
Calmels, B;Ferguson, C;Dunbar, CE
通讯作者：
Dunbar, CE