{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:20:12Z","timestamp":1790688012513,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T00:00:00Z","timestamp":1702080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["963652"],"award-info":[{"award-number":["963652"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-186300"],"award-info":[{"award-number":["PJT-186300"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fredrick Banting and Charles Best Canadian Institutes of Health Research Doctoral Research Award"},{"name":"University of Ottawa Brain and Mind Institute CNMD STAR"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by the loss of the SMN1 gene and low SMN protein levels. Current SMA therapies work by increasing SMN protein in the body. Although SMA is regarded as a motor neuron disorder, growing evidence shows that several peripheral organs contribute to SMA pathology. A gene therapy treatment, onasemnogene abeparvovec, is being explored in clinical trials via both systemic and central nervous system (CNS) specific delivery, but the ideal route of delivery as well as the long-term effectiveness is unclear. To investigate the impact of gene therapy long term, we assessed SMA mice at 6\u00a0months after treatment of either intravenous (IV) or intracerebroventricular (ICV) delivery of scAAV9-cba-SMN. Interestingly, we observed that SMN protein levels were restored in the peripheral tissues but not in the spinal cord at 6\u00a0months of age. However, ICV injections provided better motor neuron and motor function protection than IV injection, while IV-injected mice demonstrated better protection of neuromuscular junctions and muscle fiber size. Surprisingly, both delivery routes resulted in an equal rescue on survival, weight, and liver and pancreatic defects. These results demonstrate that continued peripheral AAV9-SMN gene therapy is beneficial for disease improvement even in the absence of SMN restoration in the spinal cord.<\/jats:p>","DOI":"10.1093\/hmg\/ddad202","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T09:32:53Z","timestamp":1702287173000},"page":"510-519","source":"Crossref","is-referenced-by-count":24,"title":["Long term peripheral AAV9-SMN gene therapy promotes survival in a mouse model of spinal muscular atrophy"],"prefix":"10.1093","volume":"33","author":[{"given":"Aoife","family":"Reilly","sequence":"first","affiliation":[{"name":"Regenerative Medicine Program, Ottawa Hospital Research Institute , 501, Smyth Road, Ottawa K1H 8L6 , Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa , 451 Smyth Road, Ottawa K1H 8M5 , Canada"},{"name":"Centre for Neuromuscular Disease, University of Ottawa , 451 Smyth Road, Ottawa K1H 8M5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Yaworski","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Program, Ottawa Hospital Research Institute , 501, Smyth Road, Ottawa K1H 8L6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariane","family":"Beauvais","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Program, Ottawa Hospital Research Institute , 501, Smyth Road, Ottawa K1H 8L6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard L","family":"Schneider","sequence":"additional","affiliation":[{"name":"Brain Mind Institute, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne , 1015 Lausanne , Switzerland"},{"name":"Bertarelli Platform for Gene Therapy, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne , 1202 Geneva , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9239-7310","authenticated-orcid":false,"given":"Rashmi","family":"Kothary","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Program, Ottawa Hospital Research Institute , 501, Smyth Road, Ottawa K1H 8L6 , Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa , 451 Smyth Road, Ottawa K1H 8M5 , Canada"},{"name":"Centre for Neuromuscular Disease, University of Ottawa , 451 Smyth Road, Ottawa K1H 8M5 , Canada"},{"name":"Department of Medicine, University of Ottawa , 501 Smyth Road, Ottawa K1H 8L6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,9]]},"reference":[{"key":"2024030215514011100_ref1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/nbdi.1996.0010","article-title":"The neurobiology of childhood spinal muscular atrophy","volume":"3","author":"Crawford","year":"1996","journal-title":"Neurobiol Dis"},{"key":"2024030215514011100_ref2","volume-title":"GeneReviews\u00ae","author":"Prior","year":"1993"},{"key":"2024030215514011100_ref3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"2024030215514011100_ref4","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":"2024030215514011100_ref5","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1086\/338627","article-title":"Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy","volume":"70","author":"Feldk\u00f6tter","year":"2002","journal-title":"Am J Hum Genet"},{"key":"2024030215514011100_ref6","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1080\/14737175.2017.1364159","article-title":"Nusinersen for the treatment of spinal muscular atrophy","volume":"17","author":"Chiriboga","year":"2017","journal-title":"Expert Rev Neurother"},{"key":"2024030215514011100_ref7","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1080\/14712598.2022.2066471","article-title":"Onasemnogene abeparvovec for the treatment of spinal muscular atrophy","volume":"22","author":"McMillan","year":"2022","journal-title":"Expert Opin Biol Ther"},{"key":"2024030215514011100_ref8","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s40263-022-00910-8","article-title":"Risdiplam: a review in spinal muscular atrophy","volume":"36","author":"Paik","year":"2022","journal-title":"CNS Drugs"},{"key":"2024030215514011100_ref9","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-dose gene-replacement therapy for spinal muscular atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N Engl J Med"},{"key":"2024030215514011100_ref10","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jpeds.2020.05.044","article-title":"Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1","volume":"225","author":"Feldman","year":"2020","journal-title":"J Pediatr"},{"key":"2024030215514011100_ref11","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jhep.2020.11.001","article-title":"Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy","volume":"74","author":"Chand","year":"2021","journal-title":"J Hepatol"},{"key":"2024030215514011100_ref12","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1089\/hum.2018.015","article-title":"Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN","volume":"29","author":"Hinderer","year":"2018","journal-title":"Hum Gene Ther"},{"key":"2024030215514011100_ref13","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/s41593-021-00827-3","article-title":"Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit","volume":"24","author":"Van Alstyne","year":"2021","journal-title":"Nat Neurosci"},{"key":"2024030215514011100_ref14","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000202555","article-title":"Intravenous and intrathecal onasemnogene abeparvovec gene therapy in symptomatic and presymptomatic spinal muscular atrophy: long-term follow-up study (S34.002)","volume":"100","author":"Darras","year":"2023","journal-title":"Neurology"},{"key":"2024030215514011100_ref15","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/2044-5040-3-24","article-title":"Early onset muscle weakness and disruption of muscle proteins in mouse models of spinal muscular atrophy","volume":"3","author":"Boyer","year":"2013","journal-title":"Skelet Muscle"},{"key":"2024030215514011100_ref16","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1093\/hmg\/ddu142","article-title":"Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy","volume":"23","author":"Boyer","year":"2014","journal-title":"Hum Mol Genet"},{"key":"2024030215514011100_ref17","doi-asserted-by":"crossref","first-page":"4745","DOI":"10.1093\/hmg\/ddu189","article-title":"Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics","volume":"23","author":"Bricceno","year":"2014","journal-title":"Hum Mol Genet"},{"key":"2024030215514011100_ref18","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1136\/jmg.2008.057950","article-title":"Congenital heart disease is a feature of severe infantile spinal muscular atrophy","volume":"45","author":"Rudnik-Sch\u00f6neborn","year":"2008","journal-title":"J Med Genet"},{"key":"2024030215514011100_ref19","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1093\/hmg\/ddq329","article-title":"Cardiac defects contribute to the pathology of spinal muscular atrophy models","volume":"19","author":"Shababi","year":"2010","journal-title":"Hum Mol Genet"},{"key":"2024030215514011100_ref20","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1002\/acn3.50855","article-title":"Abnormal fatty acid metabolism is a core component of spinal muscular atrophy","volume":"6","author":"Deguise","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"key":"2024030215514011100_ref21","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.ejpn.2012.01.004","article-title":"Abnormal fatty acid metabolism in spinal muscular atrophy may predispose to perioperative risks","volume":"16","author":"Zolkipli","year":"2012","journal-title":"Eur J Paediatr Neurol"},{"key":"2024030215514011100_ref22","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/ana.23582","article-title":"Glucose metabolism and pancreatic defects in spinal muscular atrophy","volume":"72","author":"Bowerman","year":"2012","journal-title":"Ann Neurol"},{"key":"2024030215514011100_ref23","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.jpeds.2015.09.023","article-title":"Responses to fasting and glucose loading in a cohort of well children with spinal muscular atrophy type II","volume":"167","author":"Davis","year":"2015","journal-title":"J Pediatr"},{"key":"2024030215514011100_ref24","first-page":"801","article-title":"Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice","volume":"26","author":"Deguise","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2024030215514011100_ref25","first-page":"932","article-title":"SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy","volume":"26","author":"Khairallah","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2024030215514011100_ref26","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/joa.12546","article-title":"Survival of motor neurone protein is required for normal postnatal development of the spleen","volume":"230","author":"Thomson","year":"2017","journal-title":"J Anat"},{"key":"2024030215514011100_ref27","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature10485","article-title":"Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model","volume":"478","author":"Hua","year":"2011","journal-title":"Nature"},{"key":"2024030215514011100_ref28","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1016\/j.ymthe.2020.05.011","article-title":"AAV9-mediated expression of SMN restricted to neurons does not rescue the spinal muscular atrophy phenotype in mice","volume":"28","author":"Besse","year":"2020","journal-title":"Mol Ther"},{"key":"2024030215514011100_ref29","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s41434-022-00338-1","article-title":"Central and peripheral delivered AAV9-SMN are both efficient but target different pathomechanisms in a mouse model of spinal muscular atrophy","volume":"29","author":"Reilly","year":"2022","journal-title":"Gene Ther"},{"key":"2024030215514011100_ref30","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1002\/acn3.51449","article-title":"Serum neurofilament light chain in pediatric spinal muscular atrophy patients and healthy children","volume":"8","author":"Nitz","year":"2021","journal-title":"Ann Clin Transl Neurol"},{"key":"2024030215514011100_ref31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1101\/gad.256644.114","article-title":"Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models","volume":"29","author":"Hua","year":"2015","journal-title":"Genes Dev"},{"key":"2024030215514011100_ref32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1089\/neu.2009.1002","article-title":"Temporal and regional changes in IGF-1\/IGF-1R Signaling in the mouse brain after traumatic brain injury","volume":"27","author":"Kizhakke Madathil","year":"2010","journal-title":"J Neurotrauma"},{"key":"2024030215514011100_ref33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/BF02740625","article-title":"The role of the insulin-like growth factors in the central nervous system","volume":"13","author":"D\u2019Ercole","year":"1996","journal-title":"Mol Neurobiol"},{"key":"2024030215514011100_ref34","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1083\/jcb.200407021","article-title":"Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model","volume":"168","author":"Dobrowolny","year":"2005","journal-title":"J Cell Biol"},{"key":"2024030215514011100_ref35","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/mt.2008.60","article-title":"Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity","volume":"16","author":"Dodge","year":"2008","journal-title":"Mol Ther"},{"key":"2024030215514011100_ref36","doi-asserted-by":"crossref","first-page":"e006103","DOI":"10.1161\/JAHA.117.006103","article-title":"The metabolic syndrome and risk of sudden cardiac death: the atherosclerosis risk in communities study","volume":"6","author":"Hess","year":"2017","journal-title":"J Am Heart Assoc"},{"key":"2024030215514011100_ref37","doi-asserted-by":"crossref","first-page":"4334","DOI":"10.1093\/hmg\/ddr360","article-title":"Reversible molecular pathology of skeletal muscle in spinal muscular atrophy","volume":"20","author":"Mutsaers","year":"2011","journal-title":"Hum Mol Genet"},{"key":"2024030215514011100_ref38","doi-asserted-by":"crossref","first-page":"8015","DOI":"10.3390\/ijms22158015","article-title":"Activation of muscle-specific kinase (MuSK) reduces neuromuscular defects in the Delta7 mouse model of spinal muscular atrophy (SMA)","volume":"22","author":"Feng","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2024030215514011100_ref39","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.3390\/ijms24021130","article-title":"Gene therapy in ALS and SMA: advances, challenges and perspectives","volume":"24","author":"Lejman","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2024030215514011100_ref40","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1093\/hmg\/ddy195","article-title":"Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy","volume":"27","author":"Groen","year":"2018","journal-title":"Hum Mol Genet"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/33\/6\/510\/56777108\/ddad202.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/33\/6\/510\/56777108\/ddad202.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,2]],"date-time":"2024-03-02T15:52:25Z","timestamp":1709394745000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/33\/6\/510\/7467301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,9]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,12,9]]},"published-print":{"date-parts":[[2024,2,28]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad202","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,3,15]]},"published":{"date-parts":[[2023,12,9]]}}}