Doi Knayo, Takeuchi Yasuhiro
MRC/UCL Centre for Medical Molecular Virology and Wohl Virion Centre, Division of infection and Immunity, University College London.
Uirusu. 2015;65(1):27-36. doi: 10.2222/jsv.65.27.
Retrovirus vectors (gammaretroviral and lentiviral vectors) have been considered as promising tools to transfer therapeutic genes into patient cells because they can permanently integrate into host cellular genome. To treat monogenic, inherited diseases, retroviral vectors have been used to add correct genes into patient cells. Conventional gammaretroviral vectors achieved successful results in clinical trials: treated patients had therapeutic gene expression in target cells and had improved symptoms of diseases. However, serious side-effects of leukemia occurred, caused by retroviral insertional mutagenesis (IM). These incidences stressed the importance of monitoring vector integration sites in patient cells as well as of re-consideration on safer vectors. More recently lentiviral vectors which can deliver genes into non-dividing cells started to be used in clinical trials including neurological disorders, showing their efficacy. Vector integration site analysis revealed that lentiviruses integrate less likely to near promoter regions of oncogenes than gammaretroviruses and no adverse events have been reported in lentiviral vector-mediated gene therapy clinical trials. Therefore lentiviral vectors have promises to be applied to a wide range of common diseases in near future. For example, T cells from cancer patients were transduced to express chimeric T cell receptors recognizing their tumour cells enhancing patients' anti-cancer immunity.
逆转录病毒载体（γ逆转录病毒载体和慢病毒载体）被认为是将治疗性基因导入患者细胞的有前途的工具，因为它们可以永久整合到宿主细胞基因组中。为了治疗单基因遗传性疾病，逆转录病毒载体已被用于将正确的基因添加到患者细胞中。传统的γ逆转录病毒载体在临床试验中取得了成功：接受治疗的患者在靶细胞中具有治疗性基因表达，并且疾病症状得到改善。然而，由逆转录病毒插入诱变（IM）引起的严重白血病副作用出现了。这些事件强调了监测患者细胞中载体整合位点以及重新考虑更安全载体的重要性。最近，能够将基因导入非分裂细胞的慢病毒载体开始用于包括神经疾病在内的临床试验，显示出它们的疗效。载体整合位点分析表明，与γ逆转录病毒相比，慢病毒整合到癌基因启动子区域附近的可能性较小，并且在慢病毒载体介导的基因治疗临床试验中没有报道不良事件。因此，慢病毒载体有望在不久的将来应用于广泛的常见疾病。例如，转导癌症患者的T细胞以表达识别其肿瘤细胞的嵌合T细胞受体，增强患者的抗癌免疫力。
