摘要
肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)是一种罕见的、致命的神经退行性疾病,其基本特征为运动神经元退化导致进行性肌肉萎缩,发病进程快,但发病机制复杂且尚不明确,为治疗性药物开发带来了极大困难。截至目前研究较为深入的病因主要包括家族遗传、蛋白错误折叠与异常聚集、细胞自噬异常、免疫系统失调、神经炎症和兴奋毒性等。美国FDA在2022年及以前批准的3款化学药均通过抗神经元兴奋毒性和抗氧化应激治疗ALS,但疗效非常有限。2023年FDA批准的1款基因疗法使ALS的治疗策略跨入了一个新阶段,但仅使少数患者受益,因此亟需深入探索ALS的发病机制并开发更有效的新型疗法。近年来针对上述几种病因开发的治疗性药物包括基因疗法、小分子化学药和抗体药物等多种类型,文章对ALS的主要发病机制及其相关治疗性药物的研究进展进行了全面、系统的综述,旨在为进一步深入探索ALS的发病机制、开发更有效的药物提供研究思路。
Amyotrophic lateral sclerosis(ALS)is a rare and fatal neurodegenerative disease characterized by the degeneration of motor neurons,leading to progressive muscle atrophy.Despite its rapid disease progression,the underlying etiological mechanisms of ALS are complex and not yet fully understood,posing significant challenges for the development of therapeutic drugs.Nowadays,the well-researched pathogenic causes primarily include familial inheritance,protein misfolding and abnormal aggregation,autophagy dysfunction,immune system dysregulation,neuroinflammation,and excitotoxicity.The US Food and Drug Administration(FDA)has approved three chemical drugs(riluzole,edaravone and sodium phenylbutrate-taurursodiol)prior to 2022,which target neuron excitotoxicity and oxidative stress to treat ALS,but their efficacy is very limited.Many studies have demonstrated that approximately 10%of ALS cases are familial,linked to mutations in genes such as superoxide dismutase 1(SOD1),chromosome 9 open reading frame 72(C9orf72),TAR DNA-binding protein(TARDBP)and fused in sarcoma(FUS).In 2023,the FDA approved a gene therapy,a kind of SOD1 antisense oligonucleotide(ASO)drug named tofersen,that has ushered ALS treatment strategies into a new phase,although it also benefits only a small number of patients.However,the remaining about 90%of ALS cases are sporadic,with notable individual variability.Therefore,there is an urgent need to further explore the pathogenesis of ALS and diversify more novel therapeutic approaches.In recent years,therapeutic drugs targeting the aforementioned causes have included various types such as gene therapies(ASO drugs,small interfering RNA and adeno-associated virus mediated microRNA or CRISPR-CasRx delivery,etc.),cell therapies(hematopoietic stem cell,mesenchymal stem cell and small extracellular vesicles,etc.),small molecule chemical drugs,and antibody drugs.This article provides a comprehensive and systematic summary of the main pathogenic mechanisms of ALS and the research progress of related therapeutic drugs,aiming to offer research insights for further exploration of the pathogenic mechanisms of ALS,the development of more effective therapeutic and diagnostic drugs and personalized treatments.
作者
姜辰霖
刘煜
JIANG Chenlin;LIU Yu(School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China)
出处
《药物生物技术》
2025年第5期713-721,共9页
Pharmaceutical Biotechnology
基金
江苏省研究生科研与实践创新计划项目(No.KYCX24_1033)。
关键词
肌萎缩侧索硬化症
遗传特征
蛋白聚集
自噬
神经炎症
兴奋毒性
治疗性药物
Amyotrophic lateral sclerosis
Genetic character
Protein aggregation
Autophagy
Neuroinflammation
Excitotoxicity
Therapeutic drugs
