mRNA药物研发的主要关键技术

Mainly key technologies in development of mRNA drugs

基于mRNA的基因治疗药物及预防疫苗已成为开发热点,其技术原理是递送至机体细胞内的mRNA,通过宿主细胞的翻译机制表达产生治疗性蛋白或免疫原蛋白,对机体产生治疗作用或刺激机体产生免疫作用。mRNA药物研发的主要关键技术如体外合成、修饰、纯化以及递送等均具有较好的通用性。通过设计合成不同的目的基因序列,结合上述高度相似的下游关键技术,可实现不同目的蛋白的体内表达,使开发出基于mRNA的标准技术体系成为可能,从而针对疾病进行预防及治疗。高效低成本体外获取目的mRNA,修饰、处理使得mRNA具备高效翻译效率的同时降低机体免疫排斥,以及将外源性mRNA高效递送至体内,解决这些问题是mRNA药物研发的重点。本文主要综述了基于mRNA药物设计的主要关键技术,如mRNA体外转录合成(in vitro transcription,IVT)、核苷及帽尾结构修饰的技术原理及研究进展,其次对mRNA纯化方法、递送系统进行了简要介绍,为mRNA基因治疗药物及疫苗开发提供支持。

Gene therapy drugs and prophylactic vaccines based on mRNA have become the focus of development.The principle of the technology is to deliver mRNA to cells of the body and express therapeutic or immunogenic proteins through the translation mechanism of host cells,so as to produce curative effect or stimulate the production of immunity.The mainly key technologies in development of mRNA drugs,such as in vitro synthesis,modification,purification and delivery,have excellent generality.Through design and synthesis of various target gene sequences,combined with the above highly similar downstream key technologies,the in vivo expression of various target proteins may be realized,making it possible to develop a standard technology system based on mRNA,so as to prevent and treat diseases.The key to development of mRNA drugs is to obtain target mRNA in vitro with high efficiency and low cost,modify and process mRNA to achieve high translation efficiency and reduce immune rejection as well as effectively deliver exogenous mRNA to the body.This paper reviews the mainly key technologies based on mRNA drug design,such as in vitro transcription(IVT)of mRNA,technological principles and research progress of nucleoside and cap tail structure modification,and briefly introduces the purification methods and delivery system of mRNA to provide a support for the development of mRNA gene drugs and vaccines.