Wong Suet Ping, Argyros Orestis, Coutelle Charles, Harbottle Richard P
Imperial College London, Gene Therapy Research Group, Molecular Medicine, Sir Alexander Fleming Building, London, UK.
Curr Opin Mol Ther. 2009 Aug;11(4):433-41.
The clinical application of gene therapy has become a reality with the treatment of patients with X-linked SCID (SCID-X1) using a modified retrovirus. This success has been tempered by the toxicity of the vector used in this trial, which led to oncogenesis in several of the treated patients. The development of safer, alternative vectors, which remain episomal and are therefore less genotoxic, is currently an area of active research. Notable recent developments include the application of modified lentiviral vectors, which stably express transgenes without the risk of integration; plasmid vectors, which exist episomally and are persistently expressed in the livers of mice; and the generation of replicating artificial chromosomes containing genomic loci. In addition, knowledge of the molecular mechanisms of nuclear retention and replication of the transgene is improving and will facilitate further developments in the use of episomal DNA for the genetic modification of cells. This review describes the development and application of gene therapy vectors, with a focus on those that are specifically designed to avoid integration and exist episomally.
使用改良逆转录病毒治疗X连锁重症联合免疫缺陷病（SCID-X1）患者，使得基因治疗的临床应用成为现实。然而，该试验中所使用载体的毒性给这一成功蒙上了阴影，它导致数名接受治疗的患者发生肿瘤。目前，开发更安全的替代载体是一个活跃的研究领域，这些载体保持游离状态，因此基因毒性较小。近期的显著进展包括应用改良的慢病毒载体，其能稳定表达转基因而无整合风险；质粒载体，其以游离状态存在并在小鼠肝脏中持续表达；以及生成包含基因组位点的复制型人工染色体。此外，对转基因核保留和复制分子机制的认识正在提高，这将促进游离DNA用于细胞基因修饰的进一步发展。本综述描述了基因治疗载体的发展与应用，重点关注那些专门设计用于避免整合并以游离状态存在的载体。
