{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T05:21:26Z","timestamp":1774675286586,"version":"3.50.1"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T00:00:00Z","timestamp":1578441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"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 motor neuron disease caused by loss of function mutations in the <jats:italic>Survival Motor Neuron 1<\/jats:italic> (<jats:italic>SMN1<\/jats:italic>) gene and reduced expression of the SMN protein, leading to spinal motor neuron death, muscle weakness and atrophy. Although humans harbour the highly homologous <jats:italic>SMN2<\/jats:italic> gene, its defective splicing regulation yields a truncated and unstable SMN protein. The first therapy for SMA was recently approved by the Food and Drug Administration and consists of an antisense oligonucleotide (<jats:italic>Nusinersen<\/jats:italic>) rendering <jats:italic>SMN2<\/jats:italic> functional and thus improving patients\u2019 motor activity and quality of life. Nevertheless, not all patients equally respond to this therapy and the long\u2010term tolerability and safety of <jats:italic>Nusinersen<\/jats:italic> are still unknown. Herein, in vivo splicing assays indicated that the HDAC inhibitor LBH589 is particularly efficient in rescuing the <jats:italic>SMN2<\/jats:italic> splicing defect in SMA fibroblasts and SMA type\u2010I mice\u2010derived neural stem cells. Western blot analyses showed that LBH589 also causes a significant increase in SMN protein expression in SMA cells. Moreover chromatin immunoprecipitation analyses revealed that LBH589 treatment induces widespread H4 acetylation of the entire <jats:italic>SMN2<\/jats:italic> locus and selectively favors the inclusion of the disease\u2010linked exon 7 in <jats:italic>SMN2<\/jats:italic> mature mRNA. The combined treatment of SMA cells with sub\u2010optimal doses of LBH589 and of an antisense oligonucleotide that mimic <jats:italic>Nusinersen<\/jats:italic> (ASO_ISSN1) elicits additive effects on <jats:italic>SMN2<\/jats:italic> splicing and SMN protein expression. These findings suggest that HDAC inhibitors can potentiate the activity of <jats:italic>Nusinersen<\/jats:italic> and support the notion that \u2018SMN\u2010plus\u2019 combinatorial therapeutic approaches might represent an enhanced opportunity in the scenario of SMA therapy.<\/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\/jnc14935-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14935","type":"journal-article","created":{"date-parts":[[2019,12,7]],"date-time":"2019-12-07T04:39:48Z","timestamp":1575693588000},"page":"264-275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Combined treatment with the histone deacetylase inhibitor LBH589 and a splice\u2010switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells"],"prefix":"10.1111","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-0675","authenticated-orcid":false,"given":"Vittoria","family":"Pagliarini","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Section of Human Anatomy Catholic University of the Sacred Heart Rome Italy"},{"name":"IRCCS Fondazione Policlinico Universitario A. Gemelli Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4531-3361","authenticated-orcid":false,"given":"Marika","family":"Guerra","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Section of Human Anatomy Catholic University of the Sacred Heart Rome Italy"},{"name":"Laboratory of Neuroembryology IRCCS Fondazione Santa Lucia Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Di Rosa","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Section of Human Anatomy Catholic University of the Sacred Heart Rome Italy"},{"name":"Laboratory of Neuroembryology IRCCS Fondazione Santa Lucia Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0877-6172","authenticated-orcid":false,"given":"Claudia","family":"Compagnucci","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroembryology IRCCS Fondazione Santa Lucia Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2864-8266","authenticated-orcid":false,"given":"Claudio","family":"Sette","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Section of Human Anatomy Catholic University of the Sacred Heart Rome Italy"},{"name":"Laboratory of Neuroembryology IRCCS Fondazione Santa Lucia Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,1,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23995"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29562"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg256"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1086\/498853"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng854"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1884910"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702752"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp313"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2011.04.010"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.160181697"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.17.2037"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10485"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1207"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm276"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.23904"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.25776"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20750"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90460-3"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/35106079"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000249142.82285.d6"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710504"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.61"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1415-47572013000300001"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.3.333"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12031"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201502059"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.19"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.447"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00741"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02919"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.4.1333-1346.2006"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2013.03.052"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI121658"},{"key":"e_1_2_10_36_1","first-page":"CD006282","article-title":"Drug treatment for spinal muscular atrophy types II and III","volume":"4","author":"Wadman R. I.","year":"2012","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12813"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.14935","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14935","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.14935","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14935","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T07:05:50Z","timestamp":1693811150000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.14935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,8]]},"references-count":36,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1111\/jnc.14935"],"URL":"https:\/\/doi.org\/10.1111\/jnc.14935","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,8]]},"assertion":[{"value":"2019-05-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}