{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:40:23Z","timestamp":1775979623908,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"17","funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS091575"],"award-info":[{"award-number":["R01NS091575"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CureSMA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced expression of the survival motor neuron (SMN) protein. Current disease-modifying therapies increase SMN levels and dramatically improve survival and motor function of SMA patients. Nevertheless, current treatments are not cures and autopsy data suggest that SMN induction is variable. Our group and others have shown that combinatorial approaches that target different modalities can improve outcomes in rodent models of SMA. Here we explore if slowing SMN protein degradation and correcting SMN splicing defects could synergistically increase SMN production and improve the SMA phenotype in model mice. We show that co-administering ML372, which inhibits SMN ubiquitination, with an SMN-modifying antisense oligonucleotide (ASO) increases SMN production in SMA cells and model mice. In addition, we observed improved spinal cord, neuromuscular junction and muscle pathology when ML372 and the ASO were administered in combination. Importantly, the combinatorial approach resulted in increased motor function and extended survival of SMA mice. Our results demonstrate that a combination of treatment modalities synergistically increases SMN levels and improves pathophysiology of SMA model mice over individual treatment.<\/jats:p>","DOI":"10.1093\/hmg\/ddac068","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T04:12:13Z","timestamp":1647922333000},"page":"2989-3000","source":"Crossref","is-referenced-by-count":7,"title":["A combinatorial approach increases SMN level in SMA model mice"],"prefix":"10.1093","volume":"31","author":[{"given":"Samantha A","family":"Dumas","sequence":"first","affiliation":[{"name":"Department of Anatomy , Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Villal\u00f3n","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center , University of Missouri, Columbia, MO 65211 , USA"},{"name":"Department of Biological Chemistry , Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth M","family":"Bergman","sequence":"additional","affiliation":[{"name":"Department of Anatomy , Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth J","family":"Wilson","sequence":"additional","affiliation":[{"name":"NIH Chemical Genomics Center , Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20892-2152 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan J","family":"Marugan","sequence":"additional","affiliation":[{"name":"NIH Chemical Genomics Center , Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20892-2152 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian L","family":"Lorson","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center , University of Missouri, Columbia, MO 65211 , USA"},{"name":"Department of Veterinary Pathobiology , College of Veterinary Medicine, University of Missouri, Columbia, MO 65211 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5001-3358","authenticated-orcid":false,"given":"Barrington G","family":"Burnett","sequence":"additional","affiliation":[{"name":"Department of Anatomy , Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"2022090105183232300_ref1","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1177\/088307389100600407","article-title":"Muscle biopsy and the clinical course of infantile spinal muscular atrophy","volume":"6","author":"Zalneraitis","year":"1991","journal-title":"J. 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A."},{"key":"2022090105183232300_ref7","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1093\/hmg\/8.7.1177","article-title":"A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2","volume":"8","author":"Monani","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"2022090105183232300_ref8","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1128\/MCB.01262-08","article-title":"Regulation of SMN protein stability","volume":"29","author":"Burnett","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"2022090105183232300_ref9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/hmg\/ddi078","article-title":"SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN","volume":"14","author":"Le","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"2022090105183232300_ref10","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.2353\/ajpath.2007.070399","article-title":"Refined characterization of the expression and stability of the SMN gene products","volume":"171","author":"Vitte","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2022090105183232300_ref11","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1136\/jmg.2010.079004","article-title":"The c.859G&gt;C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor","volume":"47","author":"Bernal","year":"2010","journal-title":"J. Med. Genet."},{"key":"2022090105183232300_ref12","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.ajhg.2009.08.002","article-title":"A positive modifier of spinal muscular atrophy in the SMN2 gene","volume":"85","author":"Prior","year":"2009","journal-title":"Am. J. Hum. 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Med."},{"key":"2022090105183232300_ref16","doi-asserted-by":"crossref","DOI":"10.3390\/jcm9072222","article-title":"New treatments in spinal muscular atrophy: positive results and new challenges","volume":"9","author":"Messina","year":"2020","journal-title":"J. Clin. Med."},{"key":"2022090105183232300_ref17","doi-asserted-by":"crossref","first-page":"e88427","DOI":"10.1172\/jci.insight.88427","article-title":"ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice","volume":"1","author":"Abera","year":"2016","journal-title":"JCI Insight"},{"key":"2022090105183232300_ref18","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.neuint.2004.04.005","article-title":"Degradation of survival motor neuron (SMN) protein is mediated via the ubiquitin\/proteasome pathway","volume":"45","author":"Chang","year":"2004","journal-title":"Neurochem. Int."},{"key":"2022090105183232300_ref19","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1093\/hmg\/ddr288","article-title":"Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice","volume":"20","author":"Kwon","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2022090105183232300_ref20","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1091\/mbc.e13-01-0042","article-title":"The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein","volume":"24","author":"Kwon","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"2022090105183232300_ref21","doi-asserted-by":"crossref","first-page":"4832","DOI":"10.1093\/hmg\/ddu198","article-title":"Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models","volume":"23","author":"Osman","year":"2014","journal-title":"Hum. Mol. 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Invest."},{"key":"2022090105183232300_ref32","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1016\/j.cca.2010.07.035","article-title":"Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) regulates the level of SMN expression through ubiquitination in primary spinal muscular atrophy fibroblasts","volume":"411","author":"Hsu","year":"2010","journal-title":"Clin. Chim. Acta"},{"key":"2022090105183232300_ref33","doi-asserted-by":"crossref","first-page":"43741","DOI":"10.1074\/jbc.M112.372318","article-title":"Ubiquitin-specific protease 9x deubiquitinates and stabilizes the spinal muscular atrophy protein-survival motor neuron","volume":"287","author":"Han","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2022090105183232300_ref34","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1021\/cn200085z","article-title":"Identification of a maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitor, BIP-135, that prolongs the median survival time of delta7 SMA KO mouse model of spinal muscular atrophy","volume":"3","author":"Chen","year":"2012","journal-title":"ACS Chem. Neurosci."},{"key":"2022090105183232300_ref35","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1091\/mbc.E17-11-0627","article-title":"Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF(Slmb) degron","volume":"29","author":"Gray","year":"2018","journal-title":"Mol. Biol. 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Dis."},{"key":"2022090105183232300_ref39","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s40478-015-0231-1","article-title":"Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn (2b\/\u2212) mouse model of spinal muscular atrophy","volume":"3","author":"Murray","year":"2015","journal-title":"Acta Neuropathol. 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