{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:17:51Z","timestamp":1792189071187,"version":"4.4.0"},"reference-count":150,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (RRC)","award":["PNRR-MCNT2-2023-12377336"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12377336"]}]},{"name":"CALabria HUB per Ricerca Innovativa ed Avanzata\u2014CALHUB.RIA, \u201cCreazione di Hub delle Scienze della Vita\u201d T4-AN-09 prog. ZRPOS2","award":["PNRR-MCNT2-2023-12377336"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12377336"]}]},{"name":"AriSLA foundation, \u201cBulb-Omics\u201d prog. ZRA124","award":["PNRR-MCNT2-2023-12377336"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12377336"]}]},{"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 progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches transforming ALS research and clinical management. We explore emerging biomarkers, including the fluid-based markers such as neurofilament light chain, exosomes, and microRNAs in biological fluids, alongside the non-fluid-based biomarkers, including neuroimaging and electrophysiological markers, for early diagnosis and patient stratification. The integration of multi-omics data reveals complex molecular mechanisms underlying ALS heterogeneity, potentially identifying novel therapeutic targets. We highlight current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR\/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood\u2013brain barrier. By bridging molecular neuroscience with bioengineering, these technologies promise to revolutionize ALS diagnosis and treatment, advancing toward truly disease-modifying interventions for this previously intractable condition.<\/jats:p>","DOI":"10.3390\/ijms26125671","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T06:19:28Z","timestamp":1749795568000},"page":"5671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6891-9879","authenticated-orcid":false,"given":"Nina","family":"Bono","sequence":"first","affiliation":[{"name":"genT_L\u039bB, Department of Chemistry, Materials and Chemical Engineering \u201cGiulio Natta\u201d, Politecnico di Milano, 20131 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3439-4625","authenticated-orcid":false,"given":"Flaminia","family":"Fruzzetti","sequence":"additional","affiliation":[{"name":"genT_L\u039bB, Department of Chemistry, Materials and Chemical Engineering \u201cGiulio Natta\u201d, Politecnico di Milano, 20131 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4177-8647","authenticated-orcid":false,"given":"Giorgia","family":"Farinazzo","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0575-068X","authenticated-orcid":false,"given":"Gabriele","family":"Candiani","sequence":"additional","affiliation":[{"name":"genT_L\u039bB, Department of Chemistry, Materials and Chemical Engineering \u201cGiulio Natta\u201d, Politecnico di Milano, 20131 Milan, Italy"},{"name":"Brain-Targeted Nanotechnologies (BraiNs) Lab, Fondazione IRCCS Istituto Neurologico Carlo Besta\u2014Politecnico di Milano, 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\u2014Politecnico di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4693","DOI":"10.1007\/s00415-024-12435-9","article-title":"Update on Recent Advances in Amyotrophic Lateral Sclerosis","volume":"271","author":"Riva","year":"2024","journal-title":"J. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3109\/17482960802566824","article-title":"Prognostic Factors in ALS: A Critical Review","volume":"10","author":"Logroscino","year":"2009","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.ncl.2015.07.001","article-title":"Familial Amyotrophic Lateral Sclerosis","volume":"33","author":"Boylan","year":"2015","journal-title":"Neurol. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/21678421.2020.1779298","article-title":"Focus on the Heterogeneity of Amyotrophic Lateral Sclerosis","volume":"21","author":"Bendotti","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rizea, R.E., Corlatescu, A.-D., Costin, H.P., Dumitru, A., and Ciurea, A.V. (2024). Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25189966"},{"key":"ref_6","first-page":"459","article-title":"Electrophysiology Test for Early ALS Diagnosis","volume":"19","author":"Kiani","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1212\/WNL.0000000000002988","article-title":"Diagnostic Criteria in Amyotrophic Lateral Sclerosis: A Multicenter Prospective Study","volume":"87","author":"Geevasinga","year":"2016","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1016\/j.clinph.2021.09.014","article-title":"Advancing Disease Monitoring of Amyotrophic Lateral Sclerosis with the Compound Muscle Action Potential Scan","volume":"132","author":"Sleutjes","year":"2021","journal-title":"Clin. Neurophysiol."},{"key":"ref_9","first-page":"e30035","article-title":"Riluzole and Edavarone: The Hope Against Amyotrophic Lateral Sclerosis","volume":"14","author":"Rokade","year":"2022","journal-title":"Cureus"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Prieto Santamar\u00eda, L., Garc\u00eda del Valle, E.P., Zanin, M., Hern\u00e1ndez Chan, G.S., P\u00e9rez Gallardo, Y., and Rodr\u00edguez-Gonz\u00e1lez, A. (2021). Classifying Diseases by Using Biological Features to Identify Potential Nosological Models. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-00554-6"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/S1474-4422(21)00465-8","article-title":"Recent Advances in the Diagnosis and Prognosis of Amyotrophic Lateral Sclerosis","volume":"21","author":"Goutman","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13024-023-00685-6","article-title":"Fluid Biomarkers for Amyotrophic Lateral Sclerosis: A Review","volume":"19","author":"Irwin","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Morello, G., Salomone, S., D\u2019Agata, V., Conforti, F.L., and Cavallaro, S. (2020). From Multi-Omics Approaches to Precision Medicine in Amyotrophic Lateral Sclerosis. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.577755"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4893","DOI":"10.1038\/s41467-024-49196-y","article-title":"Multiomic ALS Signatures Highlight Subclusters and Sex Differences Suggesting the MAPK Pathway as Therapeutic Target","volume":"15","author":"Hausmann","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_15","first-page":"699","article-title":"Biomarkers for Amyotrophic Lateral Sclerosis","volume":"35","author":"Witzel","year":"2022","journal-title":"Curr. Opin. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Giagnorio, E., Malacarne, C., Cavalcante, P., Scandiffio, L., Cattaneo, M., Pensato, V., Gellera, C., Riva, N., Quattrini, A., and Dalla Bella, E. (2023). MiR-146a in ALS: Contribution to Early Peripheral Nerve Degeneration and Relevance as Disease Biomarker. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054610"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1002\/acn3.51836","article-title":"Biomarkers in Cerebrospinal Fluid for Amyotrophic Lateral Sclerosis Phenotypes","volume":"10","author":"Zhou","year":"2023","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bonanno, S., Marcuzzo, S., Malacarne, C., Giagnorio, E., Masson, R., Zanin, R., Arnoldi, M.T., Andreetta, F., Simoncini, O., and Venerando, A. (2020). Circulating MyomiRs as Potential Biomarkers to Monitor Response to Nusinersen in Pediatric SMA Patients. Biomedicines, 8.","DOI":"10.3390\/biomedicines8020021"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s13311-016-0503-x","article-title":"Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis","volume":"14","author":"Vu","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"fcac029","DOI":"10.1093\/braincomms\/fcac029","article-title":"Multicentre Appraisal of Amyotrophic Lateral Sclerosis Biofluid Biomarkers Shows Primacy of Blood Neurofilament Light Chain","volume":"4","author":"Thompson","year":"2022","journal-title":"Brain Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s12035-019-01698-3","article-title":"Neurofilament Light Chain as a Biomarker, and Correlation with Magnetic Resonance Imaging in Diagnosis of CNS-Related Disorders","volume":"57","author":"Alirezaei","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1093\/brain\/awac394","article-title":"Neurofilament Light Chain in Drug Development for Amyotrophic Lateral Sclerosis: A Critical Appraisal","volume":"146","author":"Benatar","year":"2023","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"McCluskey, G., Morrison, K.E., Donaghy, C., Rene, F., Duddy, W., and Duguez, S. (2022). Extracellular Vesicles in Amyotrophic Lateral Sclerosis. Life, 13.","DOI":"10.3390\/life13010121"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13000-024-01473-6","article-title":"Cerebrospinal Fluid and Blood Exosomes as Biomarkers for Amyotrophic Lateral Sclerosis; A Systematic Review","volume":"19","author":"Darabi","year":"2024","journal-title":"Diagn. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"fcae268","DOI":"10.1093\/braincomms\/fcae268","article-title":"A MicroRNA Diagnostic Biomarker for Amyotrophic Lateral Sclerosis","volume":"6","author":"Banack","year":"2024","journal-title":"Brain Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"134176","DOI":"10.1016\/j.neulet.2019.03.048","article-title":"MicroRNA Expression Profiles of Neuron-Derived Extracellular Vesicles in Plasma from Patients with Amyotrophic Lateral Sclerosis","volume":"708","author":"Katsu","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102249","DOI":"10.1016\/j.nano.2020.102249","article-title":"Raman Spectroscopy Reveals Biochemical Differences in Plasma Derived Extracellular Vesicles from Sporadic Amyotrophic Lateral Sclerosis Patients","volume":"29","author":"Morasso","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Blasco, H., Veyrat-Durebex, C., Bocca, C., Patin, F., Vourc\u2019h, P., Kouassi Nzoughet, J., Lenaers, G., Andres, C.R., Simard, G., and Corcia, P. (2017). Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17389-9"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2103222","DOI":"10.1002\/advs.202103222","article-title":"Exosome Processing and Characterization Approaches for Research and Technology Development","volume":"9","author":"Lai","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chen, Y., Xia, K., Chen, L., and Fan, D. (2019). Increased Interleukin-6 Levels in the Astrocyte-Derived Exosomes of Sporadic Amyotrophic Lateral Sclerosis Patients. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00574"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dehghani, S., Ocakc\u0131, O., Hatipoglu, P.T., \u00d6zalp, V.C., and Tevlek, A. (2025). Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions. Mol. Neurobiol., 1\u201326.","DOI":"10.1007\/s12035-025-04825-5"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/nan.12541","article-title":"Invited Review: Long Non-coding RNAs: Important Regulators in the Development, Function and Disorders of the Central Nervous System","volume":"45","author":"Wei","year":"2019","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102739","DOI":"10.1016\/j.arr.2025.102739","article-title":"Fluid-Based Biomarkers for Neurodegenerative Diseases","volume":"108","author":"Cao","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"fcaa053","DOI":"10.1093\/braincomms\/fcaa053","article-title":"Identification of a Potential Non-Coding RNA Biomarker Signature for Amyotrophic Lateral Sclerosis","volume":"2","author":"Joilin","year":"2020","journal-title":"Brain Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neurobiolaging.2017.03.027","article-title":"Serum MiRNAs MiR-206, 143-3p and 374b-5p as Potential Biomarkers for Amyotrophic Lateral Sclerosis (ALS)","volume":"55","author":"Waller","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Waller, R., Wyles, M., Heath, P.R., Kazoka, M., Wollff, H., Shaw, P.J., and Kirby, J. (2018). Small RNA Sequencing of Sporadic Amyotrophic Lateral Sclerosis Cerebrospinal Fluid Reveals Differentially Expressed MiRNAs Related to Neural and Glial Activity. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00731"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41593-018-0300-4","article-title":"ALS-Implicated Protein TDP-43 Sustains Levels of STMN2, a Mediator of Motor Neuron Growth and Repair","volume":"22","author":"Klim","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Reddy, D.S., and Abeygunaratne, H.N. (2022). Experimental and Clinical Biomarkers for Progressive Evaluation of Neuropathology and Therapeutic Interventions for Acute and Chronic Neurological Disorders. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911734"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1136\/jnnp-2016-314337","article-title":"Structural MRI Correlates of Amyotrophic Lateral Sclerosis Progression","volume":"88","author":"Senda","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1111\/ene.15686","article-title":"Severity of in Vivo Corticospinal Tract Degeneration Is Associated with Survival in Amyotrophic Lateral Sclerosis: A Longitudinal, Multicohort Study","volume":"30","author":"Ta","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1136\/jnnp-2015-311952","article-title":"A Large-Scale Multicentre Cerebral Diffusion Tensor Imaging Study in Amyotrophic Lateral Sclerosis","volume":"87","author":"Turner","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103037","DOI":"10.1016\/j.nicl.2022.103037","article-title":"Graph Theory Network Analysis Provides Brain MRI Evidence of a Partial Continuum of Neurodegeneration in Patients with UMN-Predominant ALS and ALS-FTD","volume":"35","author":"Rajagopalan","year":"2022","journal-title":"Neuroimage Clin."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/ana.25520","article-title":"Presymptomatic Spinal Cord Pathology in C9orf72 Mutation Carriers: A Longitudinal Neuroimaging Study","volume":"86","author":"Querin","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"De Vocht, J., Van Weehaeghe, D., Ombelet, F., Masrori, P., Lamaire, N., Devrome, M., Van Esch, H., Moisse, M., Koole, M., and Dupont, P. (2023). Differences in Cerebral Glucose Metabolism in ALS Patients with and without C9orf72 and SOD1 Mutations. Cells, 12.","DOI":"10.3390\/cells12060933"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1007\/s00415-023-11764-5","article-title":"Presymptomatic Grey Matter Alterations in ALS Kindreds: A Computational Neuroimaging Study of Asymptomatic C9orf72 and SOD1 Mutation Carriers","volume":"270","author":"Bede","year":"2023","journal-title":"J. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1007\/s00415-022-11520-1","article-title":"Analysis of Brain and Spinal MRI Measures in a Common Domain to Investigate Directional Neurodegeneration in Motor Neuron Disease","volume":"270","author":"Toh","year":"2023","journal-title":"J. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/21678421.2021.1936062","article-title":"Muscle MRI in Motor Neuron Diseases: A Systematic Review","volume":"23","author":"Kriss","year":"2022","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5864391","DOI":"10.1155\/2023\/5864391","article-title":"PET and SPECT Imaging of ALS: An Educational Review","volume":"2023","author":"Jamali","year":"2023","journal-title":"Mol. Imaging"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chew, S., and Atassi, N. (2019). Positron Emission Tomography Molecular Imaging Biomarkers for Amyotrophic Lateral Sclerosis. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00135"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nature09819","article-title":"A Long Noncoding RNA Maintains Active Chromatin to Coordinate Homeotic Gene Expression","volume":"472","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.mric.2023.06.004","article-title":"Clinical Value of Hybrid PET\/MR Imaging: Brain Imaging Using PET\/MR Imaging","volume":"31","author":"Kas","year":"2023","journal-title":"Magn. Reson. Imaging Clin. N. Am."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s13311-016-0484-9","article-title":"Neuroimaging Endpoints in Amyotrophic Lateral Sclerosis","volume":"14","author":"Menke","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kumar, R., Waisberg, E., Ong, J., Paladugu, P., Amiri, D., Saintyl, J., Yelamanchi, J., Nahouraii, R., Jagadeesan, R., and Tavakkoli, A. (2024). Artificial Intelligence-Based Methodologies for Early Diagnostic Precision and Personalized Therapeutic Strategies in Neuro-Ophthalmic and Neurodegenerative Pathologies. Brain Sci., 14.","DOI":"10.20944\/preprints202411.1672.v1"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e38583","DOI":"10.1016\/j.heliyon.2024.e38583","article-title":"Amyotrophic Lateral Sclerosis Diagnosis Using Machine Learning and Multi-Omic Data Integration","volume":"10","author":"Su","year":"2024","journal-title":"Heliyon"},{"key":"ref_55","unstructured":"(2025, May 30). StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK430685\/."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1056\/NEJMoa070174","article-title":"Whole-Genome Analysis of Sporadic Amyotrophic Lateral Sclerosis","volume":"357","author":"Dunckley","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41588-021-00973-1","article-title":"Common and Rare Variant Association Analyses in Amyotrophic Lateral Sclerosis Identify 15 Risk Loci with Distinct Genetic Architectures and Neuron-Specific Biology","volume":"53","author":"Bakker","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1038\/nm.2901","article-title":"EPHA4 Is a Disease Modifier of Amyotrophic Lateral Sclerosis in Animal Models and in Humans","volume":"18","author":"Schoonaert","year":"2012","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Berdy\u0144ski, M., Miszta, P., Safranow, K., Andersen, P.M., Morita, M., Filipek, S., \u017bekanowski, C., and Ku\u017ama-Kozakiewicz, M. (2022). SOD1 Mutations Associated with Amyotrophic Lateral Sclerosis Analysis of Variant Severity. Sci. Rep., 12.","DOI":"10.1038\/s41598-021-03891-8"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s12035-017-0393-x","article-title":"Copy Number Variations in Amyotrophic Lateral Sclerosis: Piecing the Mosaic Tiles Together through a Systems Biology Approach","volume":"55","author":"Morello","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41593-023-01262-2","article-title":"Transcriptomics and ALS Outcome","volume":"26","author":"Floriddia","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"G\u00e1mez-Valero, A., Guisado-Corcoll, A., Herrero-Lorenzo, M., Solaguren-Beascoa, M., and Mart\u00ed, E. (2020). Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases. Antioxidants, 9.","DOI":"10.3390\/antiox9111095"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s13311-015-0340-3","article-title":"Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis","volume":"12","author":"Barmada","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"eabj0264","DOI":"10.1126\/scitranslmed.abj0264","article-title":"Genome-Wide Study of DNA Methylation Shows Alterations in Metabolic, Inflammatory, and Cholesterol Pathways in ALS","volume":"14","author":"Hop","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_65","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. Rev. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1038\/s41593-023-01374-9","article-title":"Globally Reduced N6-Methyladenosine (M6A) in C9ORF72-ALS\/FTD Dysregulates RNA Metabolism and Contributes to Neurodegeneration","volume":"26","author":"Li","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/wrna.1227","article-title":"MicroRNA in Skeletal Muscle Development, Growth, Atrophy, and Disease","volume":"5","author":"Kovanda","year":"2014","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1242\/jeb.128207","article-title":"Molecular Networks in Skeletal Muscle Plasticity","volume":"219","author":"Hoppeler","year":"2016","journal-title":"J. Exp. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1016\/j.cell.2024.02.031","article-title":"Single-Cell Dissection of the Human Motor and Prefrontal Cortices in ALS and FTLD","volume":"187","author":"Pineda","year":"2024","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1038\/s41467-023-41033-y","article-title":"Divergent Single Cell Transcriptome and Epigenome Alterations in ALS and FTD Patients with C9orf72 Mutation","volume":"14","author":"Li","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Iridoy, M.O., Zubiri, I., Zelaya, M.V., Martinez, L., Aus\u00edn, K., Lachen-Montes, M., Santamar\u00eda, E., Fernandez-Irigoyen, J., and Jeric\u00f3, I. (2019). Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010004"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"48","DOI":"10.15252\/emmm.201708202","article-title":"A Proteomic Network Approach across the ALS-FTD Disease Spectrum Resolves Clinical Phenotypes and Genetic Vulnerability in Human Brain","volume":"10","author":"Umoh","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41593-018-0294-y","article-title":"TDP-43 Extracted from Frontotemporal Lobar Degeneration Subject Brains Displays Distinct Aggregate Assemblies and Neurotoxic Effects Reflecting Disease Progression Rates","volume":"22","author":"Maniecka","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00401-019-02093-x","article-title":"Proteomics in Cerebrospinal Fluid and Spinal Cord Suggests UCHL1, MAP2 and GPNMB as Biomarkers and Underpins Importance of Transcriptional Pathways in Amyotrophic Lateral Sclerosis","volume":"139","author":"Oeckl","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s12031-019-01411-y","article-title":"Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS","volume":"69","author":"Zhu","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12014-020-09294-7","article-title":"CSF Extracellular Vesicle Proteomics Demonstrates Altered Protein Homeostasis in Amyotrophic Lateral Sclerosis","volume":"17","author":"Thompson","year":"2020","journal-title":"Clin. Proteom."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Schumacher-Schuh, A., Bieger, A., Borelli, W.V., Portley, M.K., Awad, P.S., and Bandres-Ciga, S. (2022). Advances in Proteomic and Metabolomic Profiling of Neurodegenerative Diseases. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.792227"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1136\/jnnp-2020-323611","article-title":"Untargeted Metabolomics Yields Insight into ALS Disease Mechanisms","volume":"91","author":"Goutman","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Marino, C., Grimaldi, M., Sommella, E.M., Ciaglia, T., Santoro, A., Buonocore, M., Salviati, E., Trojsi, F., Polverino, A., and Sorrentino, P. (2022). The Metabolomic Profile in Amyotrophic Lateral Sclerosis Changes According to the Progression of the Disease: An Exploratory Study. Metabolites, 12.","DOI":"10.3390\/metabo12090837"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.jtos.2024.09.005","article-title":"Metabolomics of Basal Tears in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study","volume":"34","author":"Khanna","year":"2024","journal-title":"Ocul. Surf."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Yu, M., Xu, J., Dutta, R., Trapp, B., Pieper, A.A., and Cheng, F. (2024). Network Medicine Informed Multiomics Integration Identifies Drug Targets and Repurposable Medicines for Amyotrophic Lateral Sclerosis. npj Syst. Biol. Appl., 10.","DOI":"10.1038\/s41540-024-00449-y"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/s41593-021-01006-0","article-title":"Answer ALS, a Large-Scale Resource for Sporadic and Familial ALS Combining Clinical and Multi-Omics Data from Induced Pluripotent Cell Lines","volume":"25","author":"Baxi","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"fcab242","DOI":"10.1093\/braincomms\/fcab242","article-title":"Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review and Perspective","volume":"3","author":"Wong","year":"2021","journal-title":"Brain Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/13543784.2017.1302426","article-title":"Drugs in Clinical Development for the Treatment of Amyotrophic Lateral Sclerosis","volume":"26","author":"Martinez","year":"2017","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Cook, S.F., Rhodes, T., Schlusser, C., Han, S., Chen, C., Zach, N., Murthy, V., and Dav\u00e9, S. (2021). A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.770001"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s00415-025-12975-8","article-title":"Advancements in Genetic Research and RNA Therapy Strategies for Amyotrophic Lateral Sclerosis (ALS): Current Progress and Future Prospects","volume":"272","author":"Ruffo","year":"2025","journal-title":"J. Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1021\/acs.molpharmaceut.1c00297","article-title":"Non-Viral Vector-Mediated Gene Therapy for ALS: Challenges and Future Perspectives","volume":"18","author":"Ediriweera","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1007\/BF01294721","article-title":"The Glutamate Antagonist Riluzole Suppresses Intracortical Facilitation","volume":"104","author":"Liepert","year":"1997","journal-title":"J. Neural Transm."},{"key":"ref_89","first-page":"25","article-title":"Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis","volume":"43","author":"Cruz","year":"2018","journal-title":"Pharm. Ther."},{"key":"ref_90","first-page":"216","article-title":"The Effectiveness and Value of AMX0035 and Oral Edaravone for Amyotrophic Lateral Sclerosis: A Summary from the Institute for Clinical and Economic Review\u2019s Midwest Comparative Effectiveness Public Advisory Council","volume":"29","author":"Nikitin","year":"2023","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Devinsky, O., Coller, J., Ahrens-Nicklas, R., Liu, X.S., Ahituv, N., Davidson, B.L., Bishop, K.M., Weiss, Y., and Mingorance, A. (2025). Gene Therapies for Neurogenetic Disorders. Trends Mol. Med.","DOI":"10.1016\/j.molmed.2025.01.015"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Cappella, M., Ciotti, C., Cohen-Tannoudji, M., and Biferi, M.G. (2019). Gene Therapy for ALS\u2014A Perspective. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184388"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1136\/jnnp.2009.181453","article-title":"Large-Scale SOD1 Mutation Screening Provides Evidence for Genetic Heterogeneity in Amyotrophic Lateral Sclerosis","volume":"81","author":"Dahlberg","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1474-4422(12)70043-1","article-title":"Frequency of the C9orf72 Hexanucleotide Repeat Expansion in Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Cross-Sectional Study","volume":"11","author":"Majounie","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Katyal, N., and Govindarajan, R. (2017). Shortcomings in the Current Amyotrophic Lateral Sclerosis Trials and Potential Solutions for Improvement. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00521"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1002\/mus.24198","article-title":"Genetic Heterogeneity of Amyotrophic Lateral Sclerosis: Implications for Clinical Practice and Research","volume":"49","author":"Su","year":"2014","journal-title":"Muscle Nerve"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S1474-4422(17)30401-5","article-title":"Novel Genes Associated with Amyotrophic Lateral Sclerosis: Diagnostic and Clinical Implications","volume":"17","author":"Chia","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1097\/WCO.0000000000001093","article-title":"Update on Genetics of Amyotrophic Lateral Sclerosis","volume":"35","author":"Brenner","year":"2022","journal-title":"Curr. Opin. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1097\/WCO.0000000000000737","article-title":"Update on Amyotrophic Lateral Sclerosis Genetics","volume":"32","author":"Brenner","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.gene.2015.11.049","article-title":"Mutant SOD1 Mediated Pathogenesis of Amyotrophic Lateral Sclerosis","volume":"577","author":"Kaur","year":"2016","journal-title":"Gene"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"101357","DOI":"10.1016\/j.omtm.2024.101357","article-title":"Advances in AAV-Mediated Gene Replacement Therapy for Pediatric Monogenic Neurological Disorders","volume":"32","author":"Zhou","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/0115665232316799241008073042","article-title":"Gene Augmentation Techniques to Stimulate Wound Healing Process: Progress and Prospects","volume":"25","author":"Dwivedi","year":"2024","journal-title":"Curr. Gene Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41573-022-00407-5","article-title":"Therapeutic RNA-Silencing Oligonucleotides in Metabolic Diseases","volume":"21","author":"Goga","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1056\/NEJMcibr1716741","article-title":"Finding a Treatment for ALS\u2014Will Gene Editing Cut It?","volume":"378","author":"Brown","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1016\/j.ymthe.2021.04.008","article-title":"Gene Therapy for ALS: A Review","volume":"29","author":"Amado","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1177\/0271678X251317374","article-title":"Advances in Clinical Translation of Stem Cell-Based Therapy in Neurological Diseases","volume":"45","author":"Wang","year":"2025","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Bono, N., Ponti, F., Mantovani, D., and Candiani, G. (2020). Non-Viral in Vitro Gene Delivery: It Is Now Time to Set the Bar!. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020183"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.coviro.2016.08.004","article-title":"Adeno-Associated Virus and Lentivirus Vectors: A Refined Toolkit for the Central Nervous System","volume":"21","author":"Blessing","year":"2016","journal-title":"Curr. Opin. Virol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1080\/14712598.2024.2386339","article-title":"Intraparenchymal Delivery of Adeno-Associated Virus Vectors for the Gene Therapy of Neurological Diseases","volume":"24","author":"Kumagai","year":"2024","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nm1207","article-title":"Lentiviral-Mediated Silencing of SOD1 through RNA Interference Retards Disease Onset and Progression in a Mouse Model of ALS","volume":"11","author":"Raoul","year":"2005","journal-title":"Nat. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.nbd.2011.09.014","article-title":"Viral Vectors for Gene Delivery to the Central Nervous System","volume":"48","author":"Lentz","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"35223","DOI":"10.1021\/acsomega.4c01774","article-title":"Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases","volume":"9","author":"Ozceylan","year":"2024","journal-title":"ACS Omega"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"105032","DOI":"10.1016\/j.chemphyslip.2020.105032","article-title":"Cationic Lipids for Gene Delivery: Many Players, One Goal","volume":"235","author":"Ponti","year":"2021","journal-title":"Chem. Phys. Lipids"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Tosolini, A.P., and Sleigh, J.N. (2017). Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00405"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nrd3625","article-title":"RNA Therapeutics: Beyond RNA Interference and Antisense Oligonucleotides","volume":"11","author":"Kole","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1089\/hum.2024.113","article-title":"Advances in MicroRNA Therapeutics: From Preclinical to Clinical Studies","volume":"35","author":"Brillante","year":"2024","journal-title":"Hum. Gene Ther."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Fang, T., Je, G., Pacut, P., Keyhanian, K., Gao, J., and Ghasemi, M. (2022). Gene Therapy in Amyotrophic Lateral Sclerosis. Cells, 11.","DOI":"10.3390\/cells11132066"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2003715","article-title":"Phase 1\u20132 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS","volume":"383","author":"Miller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Geng, Y., and Cai, Q. (2024). Role of C9orf72 Hexanucleotide Repeat Expansions in ALS\/FTD Pathogenesis. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1322720"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.neuron.2016.04.005","article-title":"C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS\/FTD","volume":"90","author":"Liu","year":"2016","journal-title":"Neuron"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Martier, R., and Konstantinova, P. (2020). Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.580179"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1007\/s10072-020-04773-z","article-title":"MicroRNAs in Amyotrophic Lateral Sclerosis: From Pathogenetic Involvement to Diagnostic Biomarker and Therapeutic Agent Development","volume":"41","author":"Wang","year":"2020","journal-title":"Neurol. Sci."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"4127","DOI":"10.1093\/hmg\/ddt261","article-title":"Method for Widespread MicroRNA-155 Inhibition Prolongs Survival in ALS-Model Mice","volume":"22","author":"Koval","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/ana.24618","article-title":"Adeno-associated Virus\u2013Delivered Artificial MicroRNA Extends Survival and Delays Paralysis in an Amyotrophic Lateral Sclerosis Mouse Model","volume":"79","author":"Stoica","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40035-021-00250-5","article-title":"A Perspective on Therapies for Amyotrophic Lateral Sclerosis: Can Disease Progression Be Curbed?","volume":"10","author":"Xu","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1056\/NEJMoa2005056","article-title":"SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS","volume":"383","author":"Mueller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"9779","DOI":"10.1073\/pnas.1630797100","article-title":"MicroRNAs and Small Interfering RNAs Can Inhibit MRNA Expression by Similar Mechanisms","volume":"100","author":"Zeng","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Shi, Y., Zhao, Y., Lu, L., Gao, Q., Yu, D., and Sun, M. (2023). CRISPR\/Cas9: Implication for Modeling and Therapy of Amyotrophic Lateral Sclerosis. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1223777"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00401-020-02154-6","article-title":"CRISPR Deletion of the C9ORF72 Promoter in ALS\/FTD Patient Motor Neurons Abolishes Production of Dipeptide Repeat Proteins and Rescues Neurodegeneration","volume":"140","author":"Krishnan","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"eaar3952","DOI":"10.1126\/sciadv.aar3952","article-title":"V In Vivo Genome Editing Improves Motor Function and Extends Survival in a Mouse Model of ALS","volume":"3","author":"Gaj","year":"2017","journal-title":"Sci. Adv."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/s41434-022-00375-w","article-title":"In Vivo Genome Editing Using Novel AAV-PHP Variants Rescues Motor Function Deficits and Extends Survival in a SOD1-ALS Mouse Model","volume":"30","author":"Chen","year":"2023","journal-title":"Gene Ther."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1038\/s41467-022-33332-7","article-title":"CRISPR\/Cas9-Mediated Excision of ALS\/FTD-Causing Hexanucleotide Repeat Expansion in C9ORF72 Rescues Major Disease Mechanisms in Vivo and in Vitro","volume":"13","author":"Meijboom","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.neuron.2016.09.015","article-title":"Poly(GR) in C9ORF72-Related ALS\/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in IPSC-Derived Motor Neurons","volume":"92","author":"Lu","year":"2016","journal-title":"Neuron"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.stemcr.2017.02.019","article-title":"Genetic Correction of SOD1 Mutant IPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis","volume":"8","author":"Bhinge","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/s41467-017-00911-y","article-title":"HDAC6 Inhibition Reverses Axonal Transport Defects in Motor Neurons Derived from FUS-ALS Patients","volume":"8","author":"Guo","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e100989","DOI":"10.15252\/embj.2018100989","article-title":"Abnormal TDP-43 Function Impairs Activity-Dependent BDNF Secretion, Synaptic Plasticity, and Cognitive Behavior through Altered Sortilin Splicing","volume":"38","author":"Tann","year":"2019","journal-title":"EMBO J."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.stemcr.2020.03.023","article-title":"Impairment of Mitochondrial Calcium Buffering Links Mutations in C9ORF72 and TARDBP in IPS-Derived Motor Neurons from Patients with ALS\/FTD","volume":"14","author":"Dafinca","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"5898","DOI":"10.1038\/s41467-023-41603-0","article-title":"C9orf72-ALS Human IPSC Microglia Are pro-Inflammatory and Toxic to Co-Cultured Motor Neurons via MMP9","volume":"14","author":"Vahsen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.stem.2014.03.004","article-title":"Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1","volume":"14","author":"Kiskinis","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Caron, I., Micotti, E., Paladini, A., Merlino, G., Plebani, L., Forloni, G., Modo, M., and Bendotti, C. (2015). Comparative Magnetic Resonance Imaging and Histopathological Correlates in Two SOD1 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132159"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1136\/jnnp.2009.194399","article-title":"FUS Mutations in Amyotrophic Lateral Sclerosis: Clinical, Pathological, Neurophysiological and Genetic Analysis","volume":"81","author":"Blair","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Zhao, S., Chen, R., Gao, Y., Lu, Y., Bai, X., and Zhang, J. (2023). Fundamental Roles of the Optineurin Gene in the Molecular Pathology of Amyotrophic Lateral Sclerosis. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1319706"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ejhg.2013.184","article-title":"Sequestosome-1 (SQSTM1) Sequence Variants in ALS Cases in the UK: Prevalence and Coexistence of SQSTM1 Mutations in ALS Kindred with PDB","volume":"22","author":"Kwok","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/ana.24565","article-title":"Cerebellar Neuronal Loss in Amyotrophic Lateral Sclerosis Cases with ATXN 2 Intermediate Repeat Expansions","volume":"79","author":"Tan","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.neuron.2010.11.036","article-title":"Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS","volume":"68","author":"Johnson","year":"2010","journal-title":"Neuron"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s40478-019-0758-7","article-title":"Key Role of UBQLN2 in Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"7","author":"Renaud","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature11280","article-title":"Mutations in the Profilin 1 Gene Cause Familial Amyotrophic Lateral Sclerosis","volume":"488","author":"Wu","year":"2012","journal-title":"Nature"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1311.e1","DOI":"10.1016\/j.neurobiolaging.2012.09.001","article-title":"Mutation Analysis of PFN1 in Familial Amyotrophic Lateral Sclerosis Patients","volume":"34","author":"Daoud","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nn.4000","article-title":"Haploinsufficiency of TBK1 Causes Familial ALS and Fronto-Temporal Dementia","volume":"18","author":"Freischmidt","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/ng.3626","article-title":"NEK1 Variants Confer Susceptibility to Amyotrophic Lateral Sclerosis","volume":"48","author":"Kenna","year":"2016","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5671\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:51:14Z","timestamp":1760032274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5671"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,13]]},"references-count":150,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125671"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125671","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,13]]}}}