靶向pre-mRNA的选择性剪接过程的疾病治疗策略研究概述

An overview of disease treatment strategies targeting the alternative splicing of pre-mRNA

前体信使RNA(pre-mRNA)的选择性剪接是人类转录组和蛋白质组多样性的关键机制。选择性剪接是复杂的基因调控过程,全转录组分析表明95%的人外显子基因是选择性剪接的,涉及多种顺式作用元件和反式作用因子。其中,任一环节或组分发生改变都可能引起错误剪接事件,进而导致多种相关疾病的发生。除直接改变剪接结果的基因替代治疗外,RNA剪接修饰有望成为一种新的治疗策略,通过靶向并纠正异常pre-mRNA剪接来达到缓解或治疗疾病的目的。目前所开发的剪接修饰工具有RNA反式剪接、反义寡核苷酸、小干扰RNA和小分子药物等,它们可通过不同的方式纠正异常剪接。本文综述了近年来对pre-mRNA选择性剪接的表观遗传调控研究进展,探讨了选择性剪接的发生与调节、相关的剪接缺陷导致的疾病种类以及当前用于靶向和改变剪接的工具,展望了剪接修饰策略在未来人类疾病治疗中的重要作用。

Alternative splicing of pre-messenger RNA(pre-mRNA)is a crucial mechanism for the diversity of the human transcriptome and proteome.Alternative splicing is a complex gene regulation process.Whole-transcriptome analysis shows that 95%of human exonic genes are alternatively spliced,involving various cis-acting elements and trans-acting factors.Any changes in any component or step may cause erroneous splicing events and lead to the occurrence of various related diseases.In addition to gene replacement therapy that directly changes the splicing results,RNA splicing modification is expected to become a new therapeutic strategy to alleviate or treat diseases by targeting and correcting abnormal pre-mRNA splicing.Splicing modification tools currently developed including RNA trans-splicing,antisense oligonucleotides,small interfering RNA,and small molecule drugs can correct abnormal splicing through different ways.This article reviews the resent progress of epigenetic regulation of pre-mRNA alternative splicing in recent years,and discusses the occurrence and regulation of alternative splicing,the types of diseases caused by related splicing defects,and the current-used tools for targeting and altering splicing.The importance of splicing modification strategies in the future treatment of human diseasesis envisioned.