{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T23:42:57Z","timestamp":1793922177308,"version":"4.8.0"},"reference-count":19,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000971","name":"ALS Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction\/Aims<\/jats:title>\n                    <jats:p>\n                      <jats:bold>Amyotrophic lateral sclerosis<\/jats:bold>\n                      (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC\u2010NTF), a novel autologous cell\u2010therapy capable of targeting multiple pathways, could safely slow ALS disease progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This randomized, double\u2010blind, placebo\u2010controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS\u2010R) \u226525 (screening) and\u2009\u22653 ALSFRS\u2010R points decline prior to randomization. Participants received three treatments of MSC\u2010NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC\u2010NTF through a responder analysis and safety. A change in disease progression post\u2010treatment of \u22651.25\u2009points\/mo defines a clinical response. A pre\u2010specified analysis leveraged baseline ALSFRS\u2010R of 35 as a subgroup threshold.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Overall, MSC\u2010NTF treatment was well tolerated; there were no safety concerns. Thirty\u2010three percent of MSC\u2010NTF and 28% of placebo participants met clinical response criteria at 28\u2009wk (odds ratio [OR]\u00a0=\u00a01.33,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a0.45); thus, the primary endpoint was not met. A pre\u2010specified analysis of participants with baseline ALSFRS\u2010R\u2009\u2265\u200935 (n\u00a0=\u00a058) showed a clinical response rate at 28\u2009wk of 35% MSC\u2010NTF and 16% placebo (OR\u00a0=\u00a02.6,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a0.29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC\u2010NTF, with placebo unchanged.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The study did not reach statistical significance on the primary endpoint. However, a pre\u2010specified subgroup suggests that MSC\u2010NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mus.27472","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T09:26:24Z","timestamp":1639128384000},"page":"291-302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["A randomized\n                    <scp>placebo\u2010controlled<\/scp>\n                    phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7075-1681","authenticated-orcid":false,"given":"Merit E.","family":"Cudkowicz","sequence":"first","affiliation":[{"name":"Healey Center, Mass General Hospital Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0103-2552","authenticated-orcid":false,"given":"Stacy R.","family":"Lindborg","sequence":"additional","affiliation":[{"name":"Research and Development Brainstorm Cell Therapeutics  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namita A.","family":"Goyal","sequence":"additional","affiliation":[{"name":"UCI Health ALS &amp; Neuromuscular Center University of California  Irvine CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Miller","sequence":"additional","affiliation":[{"name":"Sutter Pacific Medical Foundation California Pacific Medical Center  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Burford","sequence":"additional","affiliation":[{"name":"Department of Neurology Cedars\u2010Sinai Medical Center  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Berry","sequence":"additional","affiliation":[{"name":"Healey Center, Mass General Hospital Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine A.","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Healey Center, Mass General Hospital Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1230-0188","authenticated-orcid":false,"given":"Tahseen","family":"Mozaffar","sequence":"additional","affiliation":[{"name":"UCI Health ALS &amp; Neuromuscular Center University of California  Irvine CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan S.","family":"Katz","sequence":"additional","affiliation":[{"name":"Sutter Pacific Medical Foundation California Pacific Medical Center  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liberty J.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Sutter Pacific Medical Foundation California Pacific Medical Center  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Baloh","sequence":"additional","affiliation":[{"name":"Department of Neurology Cedars\u2010Sinai Medical Center  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-4575","authenticated-orcid":false,"given":"Richard A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Neurology Cedars\u2010Sinai Medical Center  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P.","family":"Staff","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic College of Medicine  Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Owegi","sequence":"additional","affiliation":[{"name":"Neurology Department University of Massachusetts Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald A.","family":"Berry","sequence":"additional","affiliation":[{"name":"Berry Consultants  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Gothelf","sequence":"additional","affiliation":[{"name":"Research and Development Brainstorm Cell Therapeutics  Petah Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yossef S.","family":"Levy","sequence":"additional","affiliation":[{"name":"Manufacturing Brainstorm Cell Therapeutics  Petah Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revital","family":"Aricha","sequence":"additional","affiliation":[{"name":"Research and Development Brainstorm Cell Therapeutics  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph Z.","family":"Kern","sequence":"additional","affiliation":[{"name":"Research and Development Brainstorm Cell Therapeutics  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Windebank","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic College of Medicine  Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6062-1528","authenticated-orcid":false,"suffix":"Jr","given":"Robert H.","family":"Brown","sequence":"additional","affiliation":[{"name":"Neurology Department University of Massachusetts Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1603471"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.37765\/ajmc.2020.88483"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000599"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010019\u20101554\u2010x"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008620"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2015.4321"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/146608200300079536"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u2010510x(99)00210\u20105"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2012.762930"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1198\/0003130042854"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.637"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2008"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12147"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp\u20102018\u2010319586"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.1534"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.01167"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26801"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(18)30089\u20109"},{"key":"e_1_2_11_20_1","article-title":"CSF biomarker correlations with primary outcome in NurOwn phase 3 clinical trial","author":"Cudkowicz ME","year":"2021","journal-title":"Presented by Berry JD at Northeast Amyotrophic Lateral Sclerosis Consortium\u00ae (NEALS)"}],"updated-by":[{"DOI":"10.1002\/mus.27697","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000}}],"container-title":["Muscle &amp; Nerve"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mus.27472","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mus.27472","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mus.27472","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T11:45:46Z","timestamp":1692791146000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mus.27472"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,5]]},"references-count":19,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,3]]}},"alternative-id":["10.1002\/mus.27472"],"URL":"https:\/\/doi.org\/10.1002\/mus.27472","archive":["Portico"],"relation":{},"ISSN":["0148-639X","1097-4598"],"issn-type":[{"value":"0148-639X","type":"print"},{"value":"1097-4598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,5]]},"assertion":[{"value":"2021-10-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}