基因治疗肌萎缩侧索硬化机制的研究进展

doi:10.16352/j.issn.1001-6325.2023.04.0674

基础医学与临床 ›› 2023, Vol. 43 ›› Issue (4): 674-679.doi: 10.16352/j.issn.1001-6325.2023.04.0674

基因治疗肌萎缩侧索硬化机制的研究进展

李晓光^1*, 杨璐¹, 刘旭东², 贾鑫淼², 杨欣壮², 崔丽英^1*

中国医学科学院北京协和医学院北京协和医院 1.神经科;
2.医学科学研究中心,北京 100730

收稿日期:2022-12-28 修回日期:2023-02-16 出版日期:2023-04-05 发布日期:2023-04-03
通讯作者: ^*pumchxgli@sina.com; pumchcuily@sina.com
基金资助:
国家自然科学基金(81750002);吴阶平医学基金会临床科研专项资助基金(320675017092);中国医学科学院医学与健康科技创新工程(2021I2MC&TA003);北京亦城合作发展基金会科研项目(YJXJJZ2021001406)

Progress in gene therapy mechanism of amyotrophic lateral sclerosis

LI Xiaoguang^1*, YANG Lu¹, LIU Xudong², JIA Xinmiao², YANG Xinzhuang², CUI Liying^1*

1. Department of Neurology;
2. Centre for Medical Science Research,Peking Union Medical College Hospital, CAMS & PUMC, Beijing 100730,China

Received:2022-12-28 Revised:2023-02-16 Online:2023-04-05 Published:2023-04-03
Contact: ^*pumchxgli@sina.com; pumchcuily@sina.com

摘要/Abstract

摘要： 肌萎缩侧索硬化(ALS)基因治疗研究集中在SOD1、C9ORF72、FUS、ATAX2等基因,基因变异导致的毒性功能获得是ALS的主要致病机制。针对变异基因修正主要有基因沉默和基因编辑两种策略:裸注反义寡核苷酸(ASO)诱导RNase H介导变异基因mRNA降解,或通过腺相关病毒(AAV)传递RNA干扰(RNAi)介导变异基因mRNA沉默,以减少毒性蛋白;通过CRISPR/Cas9法编辑变异基因,降低毒性蛋白。另外,通过特异性抗体及代谢调节剂降低毒性蛋白水平,以及神经保护治疗的研究也有较多进展。

关键词: 肌萎缩侧索硬化, 基因治疗, 反义寡核苷酸, RNA干扰, CRISPR/Cas9

Abstract: Gene therapy research on amyotrophic lateral sclerosis (ALS) focuses on SOD1, C9ORF72, FUS and ATAX2, et al. According to the mechanism, the pathogenicity of variant genes is mostly acquired by the toxicity gain of function. Two strategies are adopted for the silencing and editing of disease causing genes, namely, naked injection of antisense oligonucleotides (ASO) to induce the degradation of mRNA mediated by RNase H or the silencing of disease causing gene mediated by adeno-associated virus (AAV) to delivery RNA interference (RNAi) to decrease toxicity protein. CRISPR/Cas9 edits and modifies the causing gene to decrease the expression of toxic protein. In addition, there has been much progress in decreasing the level of toxic protein through specific antibodies and metabolic regulators, as well as neuroprotective therapy.

Key words: amyotrophic lateral sclerosis, gene therapy, antisense oligonucleotides, RNA interference, CRISPR-Cas9

中图分类号:

R746.4

李晓光, 杨璐, 刘旭东, 贾鑫淼, 杨欣壮, 崔丽英. 基因治疗肌萎缩侧索硬化机制的研究进展[J]. 基础医学与临床, 2023, 43(4): 674-679.

LI Xiaoguang, YANG Lu, LIU Xudong, JIA Xinmiao, YANG Xinzhuang, CUI Liying. Progress in gene therapy mechanism of amyotrophic lateral sclerosis[J]. Basic & Clinical Medicine, 2023, 43(4): 674-679.

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基因治疗肌萎缩侧索硬化机制的研究进展

Progress in gene therapy mechanism of amyotrophic lateral sclerosis

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