{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:51:51Z","timestamp":1791359511572,"version":"4.3.1"},"reference-count":163,"publisher":"Korea Society for Exercise Nutrition","issue":"3","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/2.0\/"}],"content-domain":{"domain":["e-pan.org"],"crossmark-restriction":true},"short-container-title":["Phys Act Nutr"],"published-print":{"date-parts":[[2026,9,30]]},"abstract":"<jats:p>[Purpose] A key pathological hallmark of amyotrophic lateral sclerosis (ALS) is transactive response DNA-binding protein 43 (TDP-43, encoded by &lt;i&gt;TARDBP&lt;\/i&gt;) proteinopathy. Mutations in &lt;i&gt;TARDBP&lt;\/i&gt; and cellular stress can drive nuclear clearance and cytoplasmic aggregation of TDP-43. TDP-43 is an essential nuclear RNA-binding protein that regulates RNA metabolism, and cytoplasmic TDP-43 aggregation leads to aberrant splicing of essential neuronal transcripts including stathmin-2 (&lt;i&gt;STMN2&lt;\/i&gt;) and unc-13 homolog A (&lt;i&gt;UNC13A&lt;\/i&gt;). Dysregulated RNA splicing causes cryptic exon (CE) inclusion in &lt;i&gt;STMN2&lt;\/i&gt; and &lt;i&gt;UNC13A&lt;\/i&gt; mRNA, resulting in non-functional proteins and disruption of axonal regeneration and synaptic integrity. Splice-switching antisense oligonucleotides and gene-editing platforms can correct &lt;i&gt;STMN2&lt;\/i&gt; and &lt;i&gt;UNC13A&lt;\/i&gt; mis-splicing defects. However, restoring &lt;i&gt;STMN2&lt;\/i&gt; and &lt;i&gt;UNC13A&lt;\/i&gt; expression alone is not sufficient to regenerate neuromuscular junctions or reverse skeletal muscle atrophy, both of which are crucial for functional recovery in patients with ALS.[Methods] We reviewed gene-targeted treatment strategies and rehabilitative mechanisms that inhibit ALS progression and reverse neuromuscular degeneration by analyzing databases, including Google Scholar, PubMed, and ScienceDirect. We proposed a dual-modality therapeutic approach integrating base-editing-mediated gene therapy with exercise-based rehabilitation.[Results] Antisense oligonucleotides and genome editing can restore transcript fidelity by preventing cryptic exons inclusion in &lt;i&gt;STMN2&lt;\/i&gt; and &lt;i&gt;UNC13A&lt;\/i&gt;, thereby stabilizing neuronal function. Gene-targeted therapies halt ALS progression; however, these treatments alone are insufficient to reverse neuromuscular degeneration or achieve functional recovery needed for patients with ALS to return to daily life.[Conclusion] Integrated rehabilitation is a crucial step in gene-targeted therapy for ALS. This strategy halts disease progression and restores neuromuscular function, thereby improving the lifespan and quality of life of patients with ALS.<\/jats:p>","DOI":"10.20463\/pan.2026.0045","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:23:12Z","timestamp":1790734992000},"page":"97-113","update-policy":"https:\/\/doi.org\/10.20463\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery"],"prefix":"10.20463","volume":"30","author":[{"given":"Kwangjun","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children\u2019s Hospital, Boston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taejin","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Sport Science, Korea Institute of Sport Science, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonil","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Sport Science, Korea Institute of Sport Science, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"8359","reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.182","type":"journal-article"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2024.2358786","type":"journal-article"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000343008.26874.d1","type":"journal-article"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1056\/nejmra1603471","type":"journal-article"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2009.11.018","type":"journal-article"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2009.2444","type":"journal-article"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1056\/nejm199403033300901","type":"journal-article"},{"key":"ref8","first-page":"505","type":"journal-article","volume-title":"Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial","author":"Abe","year":"2017"},{"key":"ref9","first-page":"31","type":"journal-article","volume-title":"Long\u2010term survival of participants in the CENTAUR trial of sodium phenylbutyrate\u2010taurursodiol in amyotrophic lateral sclerosis","author":"Paganoni","year":"2021"},{"key":"ref10","first-page":"130","type":"journal-article","volume-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","author":"Neumann","year":"2006"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2020-322983","type":"journal-article"},{"key":"ref12","first-page":"124","type":"journal-article","volume-title":"TDP-43 represses cryptic exon inclusion in the FTDALS gene UNC13A","author":"Ma","year":"2022"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-025-01204-5","type":"journal-article"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq5622","type":"journal-article"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1101\/2024.06.20.599684","type":"journal-article"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2019.tb00064.x","type":"journal-article"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2020.104862","type":"journal-article"},{"key":"ref18","first-page":"8523","type":"journal-article","volume-title":"Exercise-based rehabilitation on functionality and quality of life in head and neck cancer survivors. 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