Effective gene therapy with nonintegrating lentiviral vectors
Effective gene therapy with nonintegrating lentiviral vectors
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DOI：
10.1038/nm1365
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发表时间：
2006-03-01
期刊：
影响因子：
82.9
通讯作者：
Thrasher, AJ
中科院分区：
文献类型：
--
作者：
Yáñez-Muñoz, RJ;Balaggan, KS;Thrasher, AJ
逆转录病毒和慢病毒载体整合到宿主细胞染色体中携带有引起插入突变的有限机会（1）。在小鼠模型中诱发恶性肿瘤，以及在三个患有严重联合免疫缺陷的个体中发生淋巴组织增生性疾病-X1（参考文献1），突出了这种风险。2、3）。因此，基于逆转录病毒载体的临床治疗的关键挑战是实现稳定的转基因表达，同时使插入诱变最小化。最近的体外研究表明，整合缺陷型慢病毒载体可以介导稳定的转导（4-6）。使用类似的载体，我们现在在啮齿动物的眼和脑组织中显示了有效和持续的转基因体内表达。我们还显示了对视网膜变性的临床相关啮齿动物模型的实质性拯救。因此，可以在体内利用慢病毒介导的基因转移和表达的高效率，而不需要载体整合。对于有丝分裂后组织的治疗应用，该系统大大降低了插入诱变的风险。
Retroviral and lentiviral vector integration into host-cell chromosomes carries with it a finite chance of causing insertional mutagenesis(1). This risk has been highlighted by the induction of malignancy in mouse models, and development of lymphoproliferative disease in three individuals with severe combined immunodeficiency-X1 (refs. 2,3). Therefore, a key challenge for clinical therapies based on retroviral vectors is to achieve stable transgene expression while minimizing insertional mutagenesis. Recent in vitro studies have shown that integration-deficient lentiviral vectors can mediate stable transduction(4-6). With similar vectors, we now show efficient and sustained transgene expression in vivo in rodent ocular and brain tissues. We also show substantial rescue of clinically relevant rodent models of retinal degeneration. Therefore, the high efficiency of gene transfer and expression mediated by lentiviruses can be harnessed in vivo without a requirement for vector integration. For therapeutic application to postmitotic tissues, this system substantially reduces the risk of insertional mutagenesis.