Amyotrophic lateral sclerosis: a lesson in translation

Amyotrophic lateral sclerosis is associated with degeneration in motor pathways, often with extramotor involvement. Once symptoms develop, the disease is rapidly progressive, with a mean life expectancy of less than 3 years. Amyotrophic lateral sclerosis is heterogeneous. The condition forms a clinical and pathological continuum with frontotemporal dementia and overlaps with other neurodegenerative and neuropsychiatric conditions in terms of clinical features, imaging findings, neural network disruption, and genomics. 1 Goutman SA Hardiman O Al-Chalabi A et al. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol. 2022; 21: 465-479 Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar With the exception of genome-based treatments, such as tofersen 2 Miller TM Cudkowicz ME Genge A et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022; 387: 1099-1110 Crossref PubMed Scopus (221) Google Scholar that target mutations present in only a subset of people with familial amyotrophic lateral sclerosis, there are no effective treatments. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trialArimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. Full-Text PDF