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ZRA124"]}]},{"name":"European Union\u2014Next Generation EU\u2014NRRP M6C2\u2014Investment 2.1 Enhancement and strengthening of biomedical research in the NHS","award":["PNRR-MCNT2-2023-12377336"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12377336"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. One of its major genetic causes is C9ORF72, where mutations lead to hexanucleotide repeat expansions in the C9ORF72 gene. These expansions drive disease progression through mechanisms, including the formation of toxic RNAs and the accumulation of damaged proteins such as dipeptide repeats (DPRs). This review highlights these pathogenic mechanisms, focusing on RNA foci formation and the accumulation of toxic DPRs, which contribute to neuronal damage. It also discusses promising targeted therapies, including small molecules and biological drugs, designed to counteract these specific molecular events. Small molecules such as G-quadruplex stabilizers, proteasome and autophagy modulators, and RNase-targeting chimeras show potential in reducing RNA foci and DPR accumulation. Furthermore, targeting enzymes involved in repeat-associated non-AUG (RAN) translation and nucleocytoplasmic transport, which are crucial for disease pathogenesis, opens new therapeutic avenues. Even some anti-viral drugs show encouraging results in preclinical studies. Biological drugs, such as antisense oligonucleotides and gene-editing technologies like CRISPR-Cas, were explored for their potential to specifically target C9ORF72 mutations and modify the disease\u2019s molecular foundations. While preclinical and early clinical data show promise, challenges remain in optimizing delivery methods, ensuring long-term safety, and improving efficacy. This review concludes by emphasizing the importance of continued research and the potential for these therapies to alter the disease trajectory and improve patient outcomes.<\/jats:p>","DOI":"10.3390\/ijms26136268","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons"],"prefix":"10.3390","volume":"26","author":[{"given":"Marco","family":"Cattaneo","sequence":"first","affiliation":[{"name":"Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"},{"name":"PhD Program in Pharmacological Biomolecular Sciences, Experimental and Clinical, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5226-1593","authenticated-orcid":false,"given":"Eleonora","family":"Giagnorio","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lauria","sequence":"additional","affiliation":[{"name":"Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"},{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6893-6372","authenticated-orcid":false,"given":"Stefania","family":"Marcuzzo","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"},{"name":"Brain-Targeted Nanotechnologies (BraiNs) Lab, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s41582-018-0047-2","article-title":"C9orf72-mediated ALS and FTD: Multiple pathways to disease","volume":"14","author":"Balendra","year":"2018","journal-title":"Nat. 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