摘要
药物是人类抵御疾病的基本手段,千百年来人类通过不断的经验总结与技术进步,从绞而食之的古典草药到救治千万生命的青蒿素的纯化结晶,再到如今新型青蒿素的人工改造,科学技术革命一次次推进与实现着药物研发的革命性飞跃.然而无论是活性物质还是人工合成的药物分子,多是通过在蛋白水平抑制或纠正致病蛋白的相关功能,这也导致了现今依然存在许多无药可医的疾病.遗传性转甲状腺素蛋白淀粉样病变(hereditary transthyretin(TTR)amyloidosis,hATTR)是一种罕见的家族性、退行性、致命性遗传疾病,其发病率和死亡率很高.全球大约有5万名患者,平均寿命为3~15 a[1,2].该病一直无有效治疗药物,直到2018年下半年才先后诞生了两款治疗该遗传病的药物:Patisiran和Tegsedi[3~7].它们分别以RNA干扰(RNA interference,RNAi)及反义核苷酸(antisense oligotides,ASOs)的分子机制特异性降解或抑制致病基因,即TTR信使RNA(mRNA)的表达,从而减少TTR的产生.Patisiran作为世界上第一款RNAi药物,尤为引人关注,并于2018年8月在美国和欧洲先后被批准正式上市[3].Patisiran在临床上的使用代表着一种全新类型药物应用时代的开启.首款RNAi药物的获批将促进以及加速这种新型药物的研发及应用.但是RNAi药物在载体剂型上还存在着一些技术上的缺陷与不足或者是技术瓶颈[8,9].因此我们对此持有谨慎乐观的态度,期望首款RNAi药物获批所带来的历史机遇,能够使RNAi药物载体系统在技术上有重大改进或突破,在不久的将来RNAi药物可以成为真正的主流药物.
Gene therapy aims to apply biotechnological techniques to correct a defective gene through administrating therapeutic nucleic acids or editing a defective gene. The approaches used in gene therapy include traditional transgene, genome editing, such as CRISPR/CAS9, RNA interference(RNAi) and antisense oligonucleotides(ASOs), etc. Gene therapy is promising as a main approach of disease treatment in the future. Particularly, RNAi is a potential rising-star in this field. RNAi is a biological phenomenon in which small RNA molecules inhibit gene expression at post-transcriptional level. There are two categories of RNA molecules, which include small interfering RNAs(si RNAs) and micro RNAs(mi RNAs). Both RNA types can induce gene silencing through distinct mechanisms, such as degrading m RNA, decreasing m RNA stability, or preventing protein translation. The major difference between si RNAs and mi RNAs is that si RNAs are double stranded RNAs with completely paired sequences and high specificity for its targeted m RNA, whereas mi RNAs are single stranded RNAs with incomplete complementary sequences and multiple targets on m RNAs. When compared with traditional therapeutic drugs which target defective proteins, si RNA and mi RNA drugs offer advantages, such as higher specificity, lower toxicity, and easy manipulation of the defective genes of interest, etc. ASOs technique is another approach to silence a gene at the post-transcriptional level by several mechanisms including recruiting RNase H to cleave and degrade the targeted m RNA, alternative splicing, blocking translation, or binding to mi RNA to regulate gene expression. The first-ever RNAi drug was approved in the United States and Europe in 2018, a significant milestone in pharmacology which represents an era of a new type of drug. This event has been nominated as one of the top ten 2018 scientific breakthroughs. Apparently, it is expected that several other RNAi drugs will be approved for marketing in the near future. The first si RNA drug was used on a rare gen
作者
颜炳学
米玉倩
崔庆为
仝舟
Anoliefo Ijeoma Janefrancis
高山
Bingxue Yan;Yuqian Mi;Qingwei Cui;Zhou Tong;Anoliefo Ijeoma Janefrancis;Shan Gao(Shanxi Academy of Advanced Research and Innovation,Taiyuan 030032,China;MCTO Biopharma LLC,Frederick MD 21703,USA;Institute of Microbiology,Chinese Academy of Sciences,Beijing 100101,China;Suzhou Institute of Biomedical Engineering and Technology,Chinese Academy of Sciences,Suzhou 215163,China)
出处
《科学通报》
EI
CAS
CSCD
北大核心
2020年第7期540-546,共7页
Chinese Science Bulletin
基金
山西转型综合改革示范区科技创新项目(2017KJCX01)
山西“百人计划”、国家自然科学基金(81773023)
国家重点研发计划(2016YFC302100)
中国科学院B类战略性先导科技专项(XDB29040103)
中国科学院前沿科学重点研究计划(QYZDB-SSW-SMC038)
中国科学院科研仪器设备研制项目(YJKYYQ20180032)资助.
