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. 2025 Jan;24(1):77-86.
doi: 10.1016/S1474-4422(24)00479-4.

Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention

Michael Benatar  1 , Janice Robertson  2 , Peter Munch Andersen  3
Affiliations

Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention

Michael Benatar et al. Lancet Neurol. 2025 Jan.

Abstract

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.

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Conflict of interest statement

Declaration of interests MB received research funding from the National Institutes of Health (U54-NS092091, U01-NS107027, R01-NS105470, and U24-NS107376) and the Muscular Dystrophy Association (645863); serves as the Global Principal Investigator for the ATLAS trial sponsored by Biogen 233AS303; served as a Site Investigator for other clinical trials sponsored by Biogen (233AS101, 233AS102, 245AS101, and 245AS102); served as a consultant to Alector, Annexon, Arrowhead, Biogen, Denali, Eli Lilly, Novartis, Roche, uniQure, and Woolsey; reports a provision patent (Determining onset of ALS); and is an unpaid member of the Board of Trustees for the ALS Association. JR reports funding from the James Hunter and Family ALS Initiative, Canadian Institutes of Health Research, ALS Canada, and Brain Canada; and is a cofounder of Neuropeutics. PMA received research grants from the Swedish Research Council (#2017-03100), the Knut and Alice Wallenberg Foundation (#2012.0091, 2014.0305, 2020.0232, and 2023.0460), the Ulla-Carin Lindquist Foundation, NEURO, and the Brain Foundation (#2022-0309); paid consultancies and serves or has served on advisory boards for Biogen, Roche, Arrowhead, Avrion, Regeneron, uniQure, Voyager, and Orphazyme A/S; is a clinical trial Site Investigator for AB Science, AL-S Pharma and Lilly, Amylyx, Alexion Pharmaceuticals, Biogen Idec, IBT-Med, IONIS Pharmaceuticals, Orion Pharma, PTC Pharmaceuticals, Sanofi, and Novartis; is Director of the ALS-genetic laboratory at Umeå University Hospital that performs non-profit research genetic testing and free genetic testing since 1993; is an unpaid member of the ClinGen ALS Gene variant Curation Expert panel since 2021; and is an External Advisor to the European Medicine Agency.

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