{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T03:55:08Z","timestamp":1773374108721,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,6,30]],"date-time":"2015-06-30T00:00:00Z","timestamp":1435622400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,6,30]],"date-time":"2015-06-30T00:00:00Z","timestamp":1435622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (<jats:italic>SMN<\/jats:italic>) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous <jats:italic>SMN2<\/jats:italic> gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1) and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating <jats:italic>SMN2<\/jats:italic> RNA: ASO affects exon 7 splicing, TALE-TF increase <jats:italic>SMN2<\/jats:italic> RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the <jats:italic>in vitro<\/jats:italic> SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on <jats:italic>SMN2<\/jats:italic> RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as <jats:italic>in vitro<\/jats:italic> disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders.<\/jats:p>","DOI":"10.1038\/srep11746","type":"journal-article","created":{"date-parts":[[2015,6,30]],"date-time":"2015-06-30T12:00:26Z","timestamp":1435665626000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches"],"prefix":"10.1038","volume":"5","author":[{"given":"Monica","family":"Nizzardo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Simone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Dametti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Salani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianna","family":"Ulzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Pagliarani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Rizzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Frattini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franco","family":"Pagani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nereo","family":"Bresolin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Comi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,6,30]]},"reference":[{"key":"BFsrep11746_CR1","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/ng0797-265","volume":"16","author":"S Lefebvre","year":"1997","unstructured":"Lefebvre, S. et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nature genetics 16, 265\u2013269 10.1038\/ng0797-265 (1997).","journal-title":"Nature genetics"},{"key":"BFsrep11746_CR2","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.ajhg.2009.08.002","volume":"85","author":"TW Prior","year":"2009","unstructured":"Prior, T. W. et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. American journal of human genetics 85, 408\u2013413 10.1016\/j.ajhg.2009.08.002 (2009).","journal-title":"American journal of human genetics"},{"key":"BFsrep11746_CR3","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.clinthera.2013.11.006","volume":"36","author":"C Zanetta","year":"2014","unstructured":"Zanetta, C. et al. Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clinical therapeutics 36, 128\u2013140 10.1016\/j.clinthera.2013.11.006 (2014).","journal-title":"Clinical therapeutics"},{"key":"BFsrep11746_CR4","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1093\/hmg\/7.10.1531","volume":"7","author":"S Lefebvre","year":"1998","unstructured":"Lefebvre, S., Burglen, L., Frezal, J., Munnich, A. & Melki, J. The role of the SMN gene in proximal spinal muscular atrophy. Human molecular genetics 7, 1531\u20131536 (1998).","journal-title":"Human molecular genetics"},{"key":"BFsrep11746_CR5","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/nrn2670","volume":"10","author":"AH Burghes","year":"2009","unstructured":"Burghes, A. H. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nature reviews. Neuroscience 10, 597\u2013609 10.1038\/nrn2670 (2009).","journal-title":"Nature reviews. 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