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Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.<\/jats:p>","DOI":"10.3390\/biom12101431","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T00:07:43Z","timestamp":1665187663000},"page":"1431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3636-7395","authenticated-orcid":false,"given":"Francesco","family":"Errico","sequence":"first","affiliation":[{"name":"Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy"},{"name":"Department of Agricultural Sciences, University of Naples \u201cFederico II\u201d, 80055 Portici, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Marino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7354-8008","authenticated-orcid":false,"given":"Manuela","family":"Grimaldi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommaso","family":"Nuzzo","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy"},{"name":"Department of Environmental, Biological and Pharmaceutical Science and Technologies, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9439-6090","authenticated-orcid":false,"given":"Valentina","family":"Bassareo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Valsecchi","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4571-611X","authenticated-orcid":false,"given":"Chiara","family":"Panicucci","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8179-6666","authenticated-orcid":false,"given":"Elia","family":"Di Schiavi","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and BioResources (IBBR), CNR, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-8533","authenticated-orcid":false,"given":"Tommaso","family":"Mazza","sequence":"additional","affiliation":[{"name":"IRCCS Casa Sollievo della Sofferenza, Bioinformatics Unit, 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health-DINOGMI, University of Genova, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2438-2624","authenticated-orcid":false,"given":"Adele","family":"D\u2019Amico","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00163 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manolo","family":"Carta","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"D\u2019Ursi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-4590","authenticated-orcid":false,"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00163 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9168-5628","authenticated-orcid":false,"given":"Livio","family":"Pellizzoni","sequence":"additional","affiliation":[{"name":"Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA"},{"name":"Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA"},{"name":"Department of Neurology, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy"},{"name":"Department of Environmental, Biological and Pharmaceutical Science and Technologies, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8691","DOI":"10.1523\/JNEUROSCI.0417-15.2015","article-title":"Disease mechanisms and therapeutic approaches in spinal muscular atrophy","volume":"35","author":"Tisdale","year":"2015","journal-title":"J. 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