Michael Benatar, Janice Robertson, Peter Munch Andersen
{"title":"由 SOD1 变异引起的肌萎缩侧索硬化症:从基因发现到疾病预防","authors":"Michael Benatar, Janice Robertson, Peter Munch Andersen","doi":"10.1016/s1474-4422(24)00479-4","DOIUrl":null,"url":null,"abstract":"Pathogenic variants in the superoxide dismutase 1 (<em>SOD1</em>) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of <em>SOD1</em> ALS. The understanding that <em>SOD1</em> ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of <em>SOD1</em> ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest <em>SOD1</em> ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of <em>SOD1</em> ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"260 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention\",\"authors\":\"Michael Benatar, Janice Robertson, Peter Munch Andersen\",\"doi\":\"10.1016/s1474-4422(24)00479-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Pathogenic variants in the superoxide dismutase 1 (<em>SOD1</em>) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of <em>SOD1</em> ALS. The understanding that <em>SOD1</em> ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of <em>SOD1</em> ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest <em>SOD1</em> ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of <em>SOD1</em> ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.\",\"PeriodicalId\":22676,\"journal\":{\"name\":\"The Lancet Neurology\",\"volume\":\"260 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-12-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Lancet Neurology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/s1474-4422(24)00479-4\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Lancet Neurology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/s1474-4422(24)00479-4","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention
Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.