{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:38:07Z","timestamp":1792337887675,"version":"4.4.0"},"reference-count":128,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms26094063","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T04:08:24Z","timestamp":1745554104000},"page":"4063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targets and Gene Therapy of ALS (Part 1)"],"prefix":"10.3390","volume":"26","author":[{"given":"Olga","family":"Shiryaeva","sequence":"first","affiliation":[{"name":"Almazov Federal Medical Research Centre, 197341 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8172-5374","authenticated-orcid":false,"given":"Christina","family":"Tolochko","sequence":"additional","affiliation":[{"name":"Almazov Federal Medical Research Centre, 197341 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Alekseeva","sequence":"additional","affiliation":[{"name":"Almazov Federal Medical Research Centre, 197341 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8100-7367","authenticated-orcid":false,"given":"Vyacheslav","family":"Dyachuk","sequence":"additional","affiliation":[{"name":"Almazov Federal Medical Research Centre, 197341 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"fcad152","DOI":"10.1093\/braincomms\/fcad152","article-title":"Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis","volume":"5","author":"Ruf","year":"2023","journal-title":"Brain Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7929","DOI":"10.1523\/JNEUROSCI.1877-07.2007","article-title":"Mutant Cu\/Zn-Superoxide Dismutase Associated with Amyotrophic Lateral Sclerosis Destabilizes Vascular Endothelial Growth Factor mRNA and Downregulates Its Expression","volume":"27","author":"Lu","year":"2007","journal-title":"J. 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