{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:53:22Z","timestamp":1787068402131,"version":"build-2736575974"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with few treatments available. Mesenchymal stem cells have arisen as a potential treatment option for ALS due to their immune system modulation and their neuroprotective effects. This clinical trial aimed to evaluate the safety, efficacy and feasibility of three intravenous doses of autologous adipose-derived mesenchymal stem cells (AdMSC) in ALS patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A multicentre, randomized, parallel group, placebo-controlled, double-blinded clinical trial (\n                      <jats:uri>EudraCT: 2011-006254-85<\/jats:uri>\n                      ) was conducted in 40 patients with ALS in treatment with riluzole. Patients were randomized 1:1:1:1 into the following treatment groups: 1\u202f\u00d7\u202f10\n                      <jats:sup>6<\/jats:sup>\n                      \u202fcells\/kg, 2\u202f\u00d7\u202f10\n                      <jats:sup>6<\/jats:sup>\n                      cells\/kg, 4\u202f\u00d7\u202f10\n                      <jats:sup>6<\/jats:sup>\n                      cells\/kg and placebo. After a 6\u202fmonth follow-up, patients in the placebo group were randomized 1:1:1 to receive one of the three doses of AdMSC and they were followed up for another 6\u202fmonths. Lastly, all patients were followed-up in a 36-month open-label extension. Safety was mainly assessed through the evaluation of adverse events and their relationship with the medicinal product. Several variables were measured to assess efficacy, such as ALS Functional Rating Scale, Ashworth spasticity scale, neurophysiological and neuropsychological parameters and overall survival. The feasibility of the procedure was assessed through the evaluation of the extraction and infusion of AdMSC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Safety of AdMSC was observed through all follow-up periods, with similar percentages of adverse events between groups and no significant differences between groups in the rate of adverse events related to treatment. The administration procedure was feasible for all patients. Across all analyzed measures, we observed the expected progressive decline characteristic of ALS, with no statistically significant between-group differences in the rate of change.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The results obtained in this study are consistent with the ones obtained in other clinical trials using similar doses of MSC, where safety was demonstrated and efficacy results were inconclusive, due to not reaching statistical significance. Larger studies with an increased sample size, different doses and route of administration or combination of routes, repeated dosing or larger duration and comprehensive assessment of immunological effect would be needed to analyze the efficacy of AdMSC in the treatment of ALS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/search?query=2011-006254-85<\/jats:uri>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2025.1655124","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T04:17:33Z","timestamp":1759897053000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Adipose-derived mesenchymal stem cells for the treatment of Amyotrophic Lateral Sclerosis. A phase I\/II safety and efficacy clinical trial"],"prefix":"10.3389","volume":"16","author":[{"given":"Eduardo","family":"Ag\u00fcera-Morales","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria Eugenia","family":"Fern\u00e1ndez-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Navarro-Mascarell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Antonio","family":"Cabezas-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda \u00c1ngeles","family":"Pe\u00f1a-Toledo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Reyes-Garrido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Postigo-Pozo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Patrignani-Ochoa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda \u00c1ngeles","family":"Geniz-Clavijo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celedonio","family":"M\u00e1rquez-Infante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Tallon-Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Tinoco-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Padillo-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amador","family":"Valladares-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candela","family":"Caballero-Eraso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"L\u00f3pez-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Mata Alc\u00e1zar-Caballero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Leyva-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rodr\u00edguez-Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Maldonado-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Garc\u00eda-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00aaLuisa","family":"Somoza-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Quijano-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda del Mar","family":"Mac\u00edas-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Carmona-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Fern\u00e1ndez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"Fern\u00e1ndez-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature20413","article-title":"Decoding ALS: from genes to mechanism","volume":"539","author":"Taylor","year":"2016","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJMra1603471","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Brown","year":"2017","journal-title":"N Engl J Med"},{"key":"ref3","doi-asserted-by":"publisher","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":"ref4","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.3389\/fnins.2019.01310","article-title":"ALS genetics, mechanisms, and therapeutics: where are we now?","volume":"13","author":"Mejzini","year":"2019","journal-title":"Front Neurosci"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2398199","DOI":"10.1080\/07853890.2024.2398199","article-title":"From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis","volume":"56","author":"Garnier","year":"2024","journal-title":"Ann Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1277399","DOI":"10.3389\/fnins.2023.1277399","article-title":"Immunology of amyotrophic lateral sclerosis \u2013 role of the innate and adaptive immunity","volume":"17","author":"Mimic","year":"2023","journal-title":"Front Neurosci"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1093\/ije\/dyw061","article-title":"Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis","volume":"46","author":"Marin","year":"2017","journal-title":"Int J Epidemiol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1007\/s00415-019-09652-y","article-title":"Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis","volume":"267","author":"Xu","year":"2020","journal-title":"J Neurol"},{"key":"ref9","year":"2025"},{"key":"ref10","year":""},{"key":"ref11","year":"1999"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jneuroim.2009.07.011","article-title":"Evaluation of humoral immune response in adaptive immunity in ALS patients during disease progression","volume":"215","author":"Saleh","year":"2009","journal-title":"J Neuroimmunol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1111\/j.1600-0404.1988.tb03686.x","article-title":"Immunity assessment in the early stages of amyotrophic lateral sclerosis: a study of virus antibodies and lymphocyte subsets","volume":"78","author":"Provinciali","year":"1988","journal-title":"Acta Neurol Scand"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"325","DOI":"10.2174\/187152710791292657","article-title":"Involvement of immune response in the pathogenesis of amyotrophic lateral Sclerosis: a therapeutic opportunity?","volume":"9","author":"Calvo","year":"2010","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1054\/jocn.1999.0194","article-title":"Anti-GM1 ganglioside antibodies: their role in the diagnosis and pathogenesis of immune-mediated motor neuropathies","volume":"7","author":"Kornberg","year":"2000","journal-title":"J Clin Neurosci"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"430","DOI":"10.3109\/17482968.2011.585163","article-title":"Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis","volume":"12","author":"Van Blitterswijk","year":"2011","journal-title":"Amyotroph Lateral Scler"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"S40","DOI":"10.1212\/wnl.47.4_suppl_2.40s","article-title":"Autoimmunity and ALS","volume":"47","author":"Smith","year":"1996","journal-title":"Neurology"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1212\/WNL.48.5.1270","article-title":"Increased CSF glutamate following injection of ALS immunoglobulins","volume":"48","author":"La Bella","year":"1997","journal-title":"Neurology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1002\/ana.10805","article-title":"Presence of dendritic cells, MCP-1, and activated microglia\/macrophages in amyotrophic lateral sclerosis spinal cord tissue","volume":"55","author":"Henkel","year":"2004","journal-title":"Ann Neurol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1097\/NEN.0b013e3181922572","article-title":"Gene, cell, and axon changes in the familial amyotrophic lateral Sclerosis mouse sensorimotor cortex","volume":"68","author":"Kassa","year":"2009","journal-title":"J Neuropathol Exp Neurol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1007\/s00702-010-0429-0","article-title":"Motor neuron\u2013immune interactions: the vicious circle of ALS","volume":"117","author":"Barbeito","year":"2010","journal-title":"J Neural Transm"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"E10","DOI":"10.3171\/FOC\/2008\/24\/3-4\/E9","article-title":"Shifting the balance: cell-based therapeutics as modifiers of the amyotrophic lateral sclerosis\u2013specific neuronal microenvironment","volume":"24","author":"Riley","year":"2008","journal-title":"Neurosurg Focus"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/j.bbadis.2006.03.001","article-title":"Innate immunity in amyotrophic lateral sclerosis","volume":"1762","author":"Moisse","year":"2006","journal-title":"Biochim Biophys Acta"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1212\/01.wnl.0000312378.94737.45","article-title":"Natural history of young-adult amyotrophic lateral sclerosis","volume":"71","author":"Sabatelli","year":"2008","journal-title":"Neurology"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"61","DOI":"10.2147\/DNND.S135748","article-title":"Riluzole: real-world evidence supports significant extension of median survival times in patients with amyotrophic lateral sclerosis","volume":"7","author":"Hinchcliffe","year":"2017","journal-title":"Degener Neurol Neuromuscul Dis"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.it.2007.03.001","article-title":"Mesenchymal stem cells: a new strategy for immunosuppression?","volume":"28","author":"Uccelli","year":"2007","journal-title":"Trends Immunol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/nri2395","article-title":"Mesenchymal stem cells in health and disease","volume":"8","author":"Uccelli","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/S1474-4422(11)70121-1","article-title":"Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases","volume":"10","author":"Uccelli","year":"2011","journal-title":"Lancet Neurol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1001\/archneur.65.6.753","article-title":"Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis","volume":"65","author":"Kassis","year":"2008","journal-title":"Arch Neurol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"63","DOI":"10.2174\/157488811794480762","article-title":"Bone marrow mesenchymal stem cells: agents of immunomodulation and neuroprotection","volume":"6","author":"Kassis","year":"2011","journal-title":"Curr Stem Cell Res Ther"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1089\/107632701300062859","article-title":"Multilineage cells from human adipose tissue: implications for cell-based therapies","volume":"7","author":"Zuk","year":"2001","journal-title":"Tissue Eng"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"329","DOI":"10.3760\/cma.j.issn.0366-6999.20120064","article-title":"Human adipose-derived mesenchymal stem cells: a better cell source for nervous system regeneration","volume":"127","author":"Han","year":"2014","journal-title":"Chin Med J"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.omtm.2021.03.017","article-title":"Adipose-derived stem cells protect motor neurons and reduce glial activation in both in vitro and in vivo models of ALS","volume":"21","author":"Ciervo","year":"2021","journal-title":"Mol Ther Methods Clin Dev"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.neuroscience.2013.05.034","article-title":"Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model","volume":"248","author":"Marconi","year":"2013","journal-title":"Neuroscience"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/sctm.18-0223","article-title":"A combination of intrathecal and intramuscular application of human mesenchymal stem cells partly reduces the activation of necroptosis in the spinal cord of SOD1G93A rats","volume":"8","author":"\u0158eho\u0159ov\u00e1","year":"2019","journal-title":"Stem Cells Transl Med"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.nbd.2008.05.016","article-title":"Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis","volume":"31","author":"Vercelli","year":"2008","journal-title":"Neurobiol Dis"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3389\/fimmu.2012.00297","article-title":"Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion","volume":"3","author":"Eggenhofer","year":"2012","journal-title":"Front Immunol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.stem.2018.05.004","article-title":"Mesenchymal stromal cells: clinical challenges and therapeutic opportunities","volume":"22","author":"Galipeau","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"693","DOI":"10.52586\/4980","article-title":"A phase II clinical trial with repeated intrathecal injections of autologous mesenchymal stem cells in patients with amyotrophic lateral sclerosis","volume":"26","author":"Petrou","year":"2021","journal-title":"Front Biosci (Landmark Ed)"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"590","DOI":"10.5966\/sctm.2014-0212","article-title":"Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis","volume":"4","author":"Oh","year":"2015","journal-title":"Stem Cells Transl Med"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1212\/WNL.0000000000003359","article-title":"Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS","volume":"87","author":"Staff","year":"2016","journal-title":"Neurology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1002\/ana.25302","article-title":"Repeated intrathecal mesenchymal stem cells for amyotrophic lateral sclerosis","volume":"84","author":"Oh","year":"2018","journal-title":"Ann Neurol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.jns.2007.05.016","article-title":"Stem cell treatment in amyotrophic lateral Sclerosis","volume":"265","author":"Mazzini","year":"2008","journal-title":"J Neurol Sci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3389\/fnins.2020.00195","article-title":"Intramuscular injection of bone marrow stem cells in amyotrophic lateral Sclerosis patients: a randomized clinical trial","volume":"14","author":"Geijo-Barrientos","year":"2020","journal-title":"Front Neurosci"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1001\/archneurol.2010.248","article-title":"Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis","volume":"67","author":"Karussis","year":"2010","journal-title":"Arch Neurol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/S1474-4422(11)70305-2","article-title":"Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study","volume":"11","author":"Connick","year":"2012","journal-title":"Lancet Neurol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1177\/1352458517703802","article-title":"Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis","volume":"24","author":"Cohen","year":"2018","journal-title":"Mult Scler J"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1111\/cns.12759","article-title":"Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: clinical, ophthalmological and radiological assessments of safety and efficacy","volume":"23","author":"Dahbour","year":"2017","journal-title":"CNS Neurosci Ther"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.bbmt.2020.01.018","article-title":"A phase 3, single-arm, prospective study of Remestemcel-L, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease","volume":"26","author":"Kurtzberg","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1080\/146608200300079536","article-title":"El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis","volume":"1","author":"Brooks","year":"2000","journal-title":"Amyotroph Lateral Scler Other Motor Neuron Disord"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1111\/codi.12947","article-title":"Autologous skeletal-muscle-derived cell injection for anal incontinence due to obstetric trauma: a 5-year follow-up of an initial study of 10 patients","volume":"17","author":"Frudinger","year":"2015","journal-title":"Color Dis"},{"key":"ref52","first-page":"247","article-title":"Stem cell transplantation in multiple sclerosis: current status and future prospects","volume-title":"Nat Rev Neurol","author":"Martino","year":"2010"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1177\/1352458509359727","article-title":"The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the international MSCT study group","volume":"16","author":"Freedman","year":"2010","journal-title":"Mult Scler J"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/S0022-510X(99)00210-5","article-title":"The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function","volume":"169","author":"Cedarbaum","year":"1999","journal-title":"J Neurol Sci"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"178","DOI":"10.3109\/17482960903093710","article-title":"Clinical significance in the change of decline in ALSFRS-R","volume":"11","author":"Castrillo-Viguera","year":"2010","journal-title":"Amyotroph Lateral Scler"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"2838","DOI":"10.1093\/brain\/awq270","article-title":"Aids to the investigation of peripheral nerve injuries. Medical Research Council: nerve injuries research committee. His majesty\u2019s stationery office: 1942; pp. 48 (iii) and 74 figures and 7 diagrams; with aids to the examination of the peripheral nervous system. By Michael O\u2019Brien for the Guarantors of Brain. Saunders Elsevier: 2010; pp. [8] 64 and 94 figures","volume":"133","author":"Compston","year":"2010","journal-title":"Brain"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1016\/j.clinph.2018.04.748","article-title":"Motor unit number estimation (MUNE): where are we now?","volume":"129","author":"De Carvalho","year":"2018","journal-title":"Clin Neurophysiol"},{"key":"ref58","first-page":"97","article-title":"Magnetic stimulation: motor evoked potentials. The International Federation of Clinical Neurophysiology","volume":"52","author":"Rothwell","year":"1999","journal-title":"Electroencephalogr Clin Neurophysiol Suppl"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/978-1-4615-1185-4_2","article-title":"Wechsler adult intelligence scale-III","volume-title":"Understanding psychological assessment","author":"Ryan","year":"2001"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1097\/00005650-198108000-00001","article-title":"The sickness impact profile: development and final revision of a health status measure","volume":"19","author":"Bergner","year":"1981","journal-title":"Med Care"},{"key":"ref61","first-page":"540","article-title":"Preliminary trial of carisoprodol in multiple sclerosis","volume":"192","author":"Ashworth","year":"1964","journal-title":"Practitioner"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/0304-3959(75)90044-5","article-title":"The McGill pain questionnaire: major properties and scoring methods","volume":"1","author":"Melzack","year":"1975","journal-title":"Pain"},{"key":"ref63","year":"2023"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1002\/jcsm.12422","article-title":"Histaminergic transmission slows progression of amyotrophic lateral sclerosis","volume":"10","author":"Apolloni","year":"2019","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"498","DOI":"10.4062\/biomolther.2021.037","article-title":"Change in cationic amino acid transport system and effect of lysine pretreatment on inflammatory state in amyotrophic lateral Sclerosis cell model","volume":"29","author":"Latif","year":"2021","journal-title":"Biomol Ther"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"592","DOI":"10.22074\/cellj.2019.5370","article-title":"Safety, feasibility of intravenous and intrathecal injection of autologous bone marrow\u2013derived mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: an open-label phase I clinical trial","volume":"20","author":"Nabavi","year":"2019","journal-title":"Cell J"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"772","DOI":"10.22074\/cellj.2021.7984","article-title":"Safety and efficacy of allogeneic adipose tissue mesenchymal stromal cells in amyotrophic lateral sclerosis patients: single-center, prospective, open-label, single-arm clinical trial with long-term follow-up","volume":"23","author":"Nabavi","year":"2021","journal-title":"Cell J"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"e2294","DOI":"10.1212\/WNL.0000000000008620","article-title":"NurOwn, phase 2, randomized, clinical trial in patients with ALS: safety, clinical, and biomarker results","volume":"93","author":"Berry","year":"2019","journal-title":"Neurology"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/mus.27472","article-title":"A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis","volume":"65","author":"Cudkowicz","year":"2022","journal-title":"Muscle Nerve"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"e927484","DOI":"10.12659\/MSM.927484","article-title":"Repeat administration of bone marrow-derived mesenchymal stem cells for treatment of amyotrophic lateral sclerosis","volume":"26","author":"Siwek","year":"2020","journal-title":"Med Sci Monit"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1007\/s12015-020-10016-7","article-title":"Umbilical cord mesenchymal stem cells in amyotrophic lateral Sclerosis: an original study","volume":"16","author":"Barczewska","year":"2020","journal-title":"Stem Cell Rev Rep"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"647","DOI":"10.3727\/096368916X693716","article-title":"Transplantation of mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: results of phase I\/IIa clinical trial","volume":"26","author":"Sykov\u00e1","year":"2017","journal-title":"Cell Transplant"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1655124\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T19:36:38Z","timestamp":1764185798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1655124\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":72,"alternative-id":["10.3389\/fneur.2025.1655124"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1655124","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"article-number":"1655124"}}