SOD1-ALS from Gene Discovery to Targeted Therapeutics: A Comprehensive Review

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons that results in progressive motor impairment. ALS is a terminal condition with a typical life expectancy of less than 2–5 years from symptom onset. Approximately 15% of ALS cases are familial. Just over 30 years ago, mutations in superoxide dismutase 1 (SOD1) were identified as a cause of familial ALS (fALS). Today, SOD1-ALS remains the second most common cause of fALS behind fALS associated with pathogenic expansions in C9orf72 in European and North American populations. Over the last 30 years, extensive research into the pathogenesis of SOD1-ALS and potential therapeutic targets has recently culminated in the first US Food and Drug Administration (FDA)-approved therapy for SOD1-ALS, tofersen, an antisense oligonucleotide (ASO). This article will review the SOD1 gene, its role in the pathogenesis of SOD1-ALS, clinical features of SOD1-ALS, the concept of ASO treatments in genetic disorders, preclinical studies and the phase I–III tofersen clinical trials, as well as ongoing/future SOD1-ALS studies.