Current and emerging approaches to the treatment of amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons, leading to progressive muscle weakness, skeletal muscle atrophy, and eventual respiratory failure. Despite significant advances in understanding the molecular mechanisms underlying the disease, effective pathogenetic treatments remain limited. This review summarizes current data on pharmacological and experimental approaches to ALS therapy. We discuss the mechanisms of action and clinical efficacy of approved drugs, including riluzole and edaravone, as well as the targeted genetic therapy tofersen, developed for patients with mutations in the SOD1 gene. Special attention is given to the combination of sodium phenylbutyrate and taurursodiol (AMX0035), which was initially approved based on the results of the CENTAUR trial but was subsequently voluntarily withdrawn following negative results from the confirmatory phase III trial (PHOENIX). Furthermore, we analyze promising therapeutic avenues currently at various stages of clinical investigation. These include anti-inflammatory and immunomodulatory agents, mitochondrial neuroprotectants, cell-based technologies, and targeted genetic strategies such as antisense oligonucleotides and gene therapy. It is emphasized that current therapeutic interventions only provide a moderate slowing of disease progression, a limitation attributed to the pronounced pathogenetic heterogeneity of ALS and its late diagnosis. Consequently, future progress in treating ALS is expected to hinge on earlier disease detection, the implementation of molecular biomarkers, and the development of personalized, combination treatment strategies targeting the various components of its pathogenesis.

About the authors

D. V. Shevchuk

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: dvlshev@gmail.com
ORCID iD: 0009-0002-1334-9730
Russian Federation, 80 Volokolamskoe Shosse, Моscow 125367

A. A. Abramova

Russian Center of Neurology and Neurosciences

Email: dvlshev@gmail.com
ORCID iD: 0000-0002-7960-1006
Russian Federation, 80 Volokolamskoe Shosse, Моscow 125367

M. N. Zakharova

Russian Center of Neurology and Neurosciences

Email: dvlshev@gmail.com
ORCID iD: 0000-0002-1072-9968
Russian Federation, 80 Volokolamskoe Shosse, Моscow 125367

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