{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T06:07:19Z","timestamp":1778220439909,"version":"3.51.4"},"reference-count":15,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T00:00:00Z","timestamp":1581638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Intramural research funds"],"award-info":[{"award-number":["Intramural research funds"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007802","name":"Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica","doi-asserted-by":"publisher","award":["MLOpathy"],"award-info":[{"award-number":["MLOpathy"]}],"id":[{"id":"10.13039\/501100007802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007802","name":"Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica","doi-asserted-by":"publisher","award":["Target_RAN"],"award-info":[{"award-number":["Target_RAN"]}],"id":[{"id":"10.13039\/501100007802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003197","name":"Agenzia Italiana del Farmaco, Ministero della Salute","doi-asserted-by":"publisher","award":["Co_ALS"],"award-info":[{"award-number":["Co_ALS"]}],"id":[{"id":"10.13039\/501100003197","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013278","name":"EU Joint Programme \u2013 Neurodegenerative Disease Research","doi-asserted-by":"publisher","award":["01ED1601A, CureALS"],"award-info":[{"award-number":["01ED1601A, CureALS"]}],"id":[{"id":"10.13039\/100013278","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP19218"],"award-info":[{"award-number":["GGP19218"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2014\u20100686"],"award-info":[{"award-number":["2014\u20100686"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Spinal muscular atrophy (SMA) is a severe autosomal recessive motor neuron disease caused by the loss of <jats:italic>SMN1<\/jats:italic>, which encodes a protein essential for motor neuron survival. SMA patients have one or more copies of an alternate <jats:italic>SMN<\/jats:italic> gene, <jats:italic>SMN2<\/jats:italic>, which is nearly identical to <jats:italic>SMN1<\/jats:italic>. <jats:italic>SMN2<\/jats:italic> differs at a single nucleotide from <jats:italic>SMN1<\/jats:italic> which results in the skipping of exon 7 in the mRNA and produces an unstable protein (SMN\u03947). Therapeutic approaches that have been undertaken include (1) replacement of <jats:italic>SMN1<\/jats:italic> by gene delivery mediated by adeno\u2010associated virus serotype 9 (AAV9) (Zolgensma), (2) correction of the aberrant <jats:italic>SMN2<\/jats:italic> splicing using an antisense oligonucleotide (ASO) or small molecule (nusinersin, risdiplam), and (3) increased expression of <jats:italic>SMN2<\/jats:italic> mediated by histone deacetylase (HDAC) inhibitors. Two of these three approaches have given rise to successful treatments for SMA, but they are very expensive, and their long\u2010term safety is not well known. In addition, the ability of ASOs and viral vectors to reach their targets in the CNS with peripheral administration is limited. Small molecules may cross the brain\u2013blood barrier when orally delivered and can be discontinued if needed to mitigate adverse effects. This Editorial highlights this study by Pagliarni et al. in which they used combined treatment of cell models of SMA with an ASO and an orally delivered HDAC inhibitor (panobinostat) to overcome the limitations of a single\u2010therapeutic approach. Panobinostat enhanced the expression of <jats:italic>SMN2<\/jats:italic>, increasing the amount of <jats:italic>SMN2<\/jats:italic> mRNA available for splicing correction mediated by the ASO. In addition, panobinostat increased exon 7 retention in the <jats:italic>SMN2<\/jats:italic> mRNA. This combinatorial treatment might allow lower or less frequent ASO doses, reducing the need for repeated intrathecal administration. The combined effects of panobinostat and nusinersen can now be tested in SMA animal models to determine whether this approach will be translatable to patients.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14974-fig-0002-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14974","type":"journal-article","created":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T08:14:57Z","timestamp":1581668097000},"page":"146-149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Combinatorial treatment for spinal muscular atrophy"],"prefix":"10.1111","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8883-0468","authenticated-orcid":false,"given":"Angelo","family":"Poletti","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari Centre of Excellence on Neurodegenerative Diseases Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8316-6895","authenticated-orcid":false,"given":"Kenneth H.","family":"Fischbeck","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch National Institute for Neurological Disorders and Stroke National Institutes of Health Bethesda MD 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\u2018Combined treatment with the histone deacetylase inhibitor LBH589 and a splice\u2010switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells\u2019 on page 264."],"short-title":[],"issued":{"date-parts":[[2020,2,14]]},"references-count":15,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1111\/jnc.14974"],"URL":"https:\/\/doi.org\/10.1111\/jnc.14974","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,14]]},"assertion":[{"value":"2020-01-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication 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