As Understanding of ALS Grows, Novel Therapies Anticipated

Since the discovery of SOD1 nearly 30 years ago, the identification of genes linked with amyotrophic lateral sclerosis (ALS) has progressed from a fairly slow start to the current period of quickly emerging insight, according to a review article published in Lancet Neurology.

Specific advances of interest include the identification of new genes associated with ALS and other neurodegenerative diseases, the influence of environmental exposures, and novel therapeutic options, explained lead author Stephen A. Goutman, MD, of the neurology department at the University of Michigan, Ann Arbor, and an international team of coauthors.

“Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors,” the authors advised.

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Improvements in genetic technology have paved the way for the rapid identification of numerous genes associated with ALS and a more comprehensive grasp of oligogenic and polygenic risk, the review indicates.

“The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations,” the authors wrote. “A deepening knowledge of the genetic architecture is allowing the characterization of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways.”

The paper also reports on the emergence of the gene-time-environment hypothesis of ALS, which positions the “exposome”, or the summation of environmental exposures over the lifetime, as an influential component of the disease.

“Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options,” the authors wrote, “an approach in use for other neurological illnesses.”

Reference

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(5):465-479. doi: 10.1016/S1474-4422(21)00414-2.