基因治疗:过去、现在和未来

Gene Therapy:Past,Present and Future

基因治疗最初的概念是将包含正常基因的DNA序列通过载体导入细胞内以矫正由于该基因缺陷所导致的疾病。由于这个概念非常直观且易于接受,而临床上众多基因缺陷导致的遗传性疾病基本无药可治,因此基因治疗产生伊始便受到了高度关注。随着20世纪七八十年代以来基因工程技术的长足发展,基因治疗从实验室研究进入了临床探索,并于1990年完成了第一个基因治疗的临床试验,进入了一个高速发展期。10年后由于美国的一项基因治疗临床试验发生了患者的意外死亡,全球的基因治疗研究明显放缓。基因治疗的重新兴起以美国食品药品管理局(FDA)批准的治疗Leber先天性黑朦的Luxturna(2017)和用于治疗脊髓性肌萎缩症(SMA)的Zolgensma(2019)上市为标志,疗效确切、价格昂贵的基因药物终于成为临床医生手中能够为以往束手无策的患者解除病痛的有力武器。而除了基因替代性基因补充疗法,针对临床不同需求的基因编辑性基因矫正疗法、基于反义寡核苷酸和小干扰RNA的基因抑制疗法、基于基因开关的基因调控疗法等多种基因治疗方法均在综合研发中。为促进我国基因治疗的发展,本研究概述了基因治疗的发展过程和近年来的发展现状,并展望了基因治疗未来的发展。

The original concept of gene therapy was to introduce DNA sequences containing normal gene through vectors into cells to correct diseases caused by defects in that gene.Because this concept was very intuitive and easy to be accepted,and the genetic diseases caused by numerous gene mutations were largely untreatable,gene therapy had received great attention as soon as it was proposed.With the rapid development of genetic engineering since the 1970s,gene therapy had entered clinical exploration from laboratory research.The first gene therapy clinical trial was completed in 1990,entering a period of rapid development.A decade later,global gene therapy research slowed down markedly as a patient died unexpectedly in a gene therapy trial in the United States.The resurgence of gene therapy US FDA-approved for the Luxturna(2017)treatment of Leber sysdroms and Zolgensma(2019)for treatment of spinal muscular atrophy(SMA)is marked by the which was a sign that effective and expensive genetic drugs have finally become a powerful weapon in the hands of clinicians to the pain of previously helpless patients.In addition to gene replacement therapy,gene editing therapy for different clinical needs,gene inhibition therapy based on antisense oligonucleotide and small interfering RNA,gene regulatable therapy based on gene switch,and other gene therapy methods are in comprehensive research and development.This paper summarizes the development process of gene therapy,its development inrecent years,and its further advancement and application in the future.