Targets and Gene Therapy of ALS (Part 1).

1. Int J Mol Sci. 2025 Apr 25;26(9):4063. doi: 10.3390/ijms26094063. Targets and Gene Therapy of ALS (Part 1). Shiryaeva O(1), Tolochko C(1), Alekseeva T(1), Dyachuk V(1). Author information: (1)Almazov Federal Medical Research Centre, 197341 Saint Petersburg, Russia. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as SOD1, C9orf72, FUS, and TARDBP has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials. DOI: 10.3390/ijms26094063 PMCID: PMC12071412 PMID: 40362304 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no conflict of interest.