基因治疗的现状与临床研究进展

Current Situation and Clinical Research Progresses of Gene Therapy

基因治疗在恶性肿瘤、代谢疾病、感染性疾病、遗传病及罕见病治疗方面有着非常重要的意义。广义的基因治疗一般包括基于质粒DNA、RNA干扰(RNA interference,RNAi)和信使RNA(messenger RNA, mRNA)等技术。20世纪90年代,基于质粒DNA的基因治疗发展迅速,直到1999年9月出现了第一个基因治疗受试病人的死亡案例,使得该领域进入沉寂期。与此同时,基于反义核酸技术、RNAi技术的研究与应用迅速崛起。1998年,Andrew Fire和Craig C. Mello首次发现并提出RNAi的概念,并于2006年获得诺贝尔奖。近些年,基于mRNA的基因疗法开始成为重要的研究热点和发展方向,利用mRNA作为疫苗和药物来预防、诊断和治疗某些疾病正逐渐成为制药企业关注的焦点。该综述分别介绍了(1)基因治疗的发展历程;(2)RNAi工作原理、发展历程、现存问题及面临挑战等;(3)mRNA基因治疗技术的发展历程、优势、递送方式、面临的问题等,同时还总结了目前全球小干扰RNA (small interfering RNA, siRNA)药物、mRNA药物临床研究现状及该领域关键技术的最新进展。

Gene therapy is of great importance in the treatment of malignant tumors, metabolic diseases, infectious diseases, genetic diseases and rare diseases. Gene therapy generally includes using plasmid DNA, RNA interference (RNAi) and messenger RNA (mRNA) techniques for therapeutic purposes. In the 1990s, gene therapy based on plasmid DNA developed rapidly. However, the first death case of the gene therapy trial in September 1999 silenced the field from then on. At the same time, antisense nucleic acid and RNAi technology have emerged. In 1998, Andrew Fire and Craig C. Mello first discovered and proposed the concept of RNAi and won the Nobel Prize in 2006. In recent years, mRNA therapy has become an important research and drug development direction. Using mRNA as vaccine and medicine to prevent and treat certain diseases is gradually becoming the focus of pharmaceutical companies. This review introduces (1) the development history of gene therapy;(2) the working principle, development history, existing problems and challenges of RNAi;(3) the development history, advantages, delivery methods and problems of mRNA technology. In addition, it also summarizes the current global state of the small interfering RNA (siRNA) and mRNA drugs in clinical research and the latest progress of key technologies in these fields.