Department of Translational Oncology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Viruses. 2011 May;3(5):429-55. doi: 10.3390/v3050429. Epub 2011 Apr 29.
The curative potential of retroviral vectors for somatic gene therapy has been demonstrated impressively in several clinical trials leading to sustained long-term correction of the underlying genetic defect. Preclinical studies and clinical monitoring of gene modified hematopoietic stem and progenitor cells in patients have shown that biologically relevant vector induced side effects, ranging from in vitro immortalization to clonal dominance and oncogenesis in vivo, accompany therapeutic efficiency of integrating retroviral gene transfer systems. Most importantly, it has been demonstrated that the genotoxic potential is not identical among all retroviral vector systems designed for clinical application. Large scale viral integration site determination has uncovered significant differences in the target site selection of retrovirus subfamilies influencing the propensity for inducing genetic alterations in the host genome. In this review we will summarize recent insights gained on the mechanisms of insertional mutagenesis based on intrinsic target site selection of different retrovirus families. We will also discuss examples of side effects occurring in ongoing human gene therapy trials and future prospectives in the field.
逆转录病毒载体在体基因治疗中的疗效已在多项临床试验中得到了显著证实，这些试验导致了潜在遗传缺陷的持续长期纠正。对基因修饰的造血干细胞和祖细胞在患者中的临床前研究和临床监测表明，生物相关的载体诱导的副作用，从体外永生化到体内的克隆优势和癌变，伴随着整合逆转录病毒基因转移系统的治疗效率。最重要的是，已经证明，并非所有设计用于临床应用的逆转录病毒载体系统的遗传毒性潜力都是相同的。大规模病毒整合位点测定揭示了不同逆转录病毒亚家族的靶位选择在影响宿主基因组中诱导遗传改变的倾向性方面存在显著差异。在这篇综述中，我们将总结基于不同逆转录病毒家族内在靶位选择的插入诱变机制的最新研究进展。我们还将讨论正在进行的人类基因治疗试验中出现的副作用实例和该领域的未来前景。
