{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:40:10Z","timestamp":1784205610775,"version":"3.55.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000},"content-version":"vor","delay-in-days":224,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SMA Europe and LifeArc\/Chief Scientific Office Scotland"},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the Survival of Motor Neuron 1 gene lead to a loss of survival motor neuron protein in patients with spinal muscular atrophy. Revolutionary advances in gene therapy have led to survival motor neuron-replacement therapies that significantly prolong life expectancy and improve neuromuscular function. However, accumulating evidence suggests that the timing of survival motor neuron-replacement therapies is a critical determinant of success. We performed a systematic review and meta-analysis of all pre-clinical studies testing survival motor neuron replacement therapies in mouse models of spinal muscular atrophy to assess the impact of timing of delivery on therapeutic effectiveness. We incorporated four databases in this pre-registered study (PROSPERO 2020 CRD42020200180): EMBASE, PubMed, Scopus and Web of Science. Inclusion criteria were; primary research article, a measure of survival analysis, use of survival motor neuron mouse model and evaluation of survival motor neuron-targeting therapy. Exclusion criteria included; use of therapies not known to directly target survival motor neuron, genetic manipulations and\/or lack of appropriate controls. We screened papers using the SyRF platform. The main outcome we assessed was survival in treated groups compared to untreated groups. We performed meta-analysis of survival using median survival ratio and the random effects model and measured heterogeneity using the I2 statistic. Subgroup analyses were performed to assess treatment efficacy based on timing of intervention (embryonic delivery, day of birth, postnatal day 2 and postnatal day 3 or later) and treatment type. If detailed in the studies, body weight compared to untreated spinal muscular atrophy models and motor neuron number were included as secondary outcomes for meta-analysis. 3469 studies were initially identified, with 78 ultimately included. Survival motor neuron-replacement therapies significantly affected survival in favour of treatment by a factor of 1.20 (95% CI 1.10\u20131.30, P &amp;lt; 0.001) with high heterogeneity (I2 = 95%). Timing of treatment was a significant source of heterogeneity (P &amp;lt; 0.01), with earlier treatment having a greater impact on survival. When stratified by type of treatment, earlier treatment continued to have the strongest effect with viral vector replacement therapy and antisense oligonucleotide therapy. Secondary outcome measures of body weight and spinal motor neuron counts were also positively associated with early treatment. Earlier delivery of survival motor neuron replacement therapies is therefore a key determinant of treatment efficacy in spinal muscular atrophy.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae267","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T18:19:48Z","timestamp":1723486788000},"source":"Crossref","is-referenced-by-count":5,"title":["Timing of SMN replacement therapies in mouse models of spinal muscular atrophy: a systematic review and meta-analysis"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2257-7620","authenticated-orcid":false,"given":"Helena","family":"Chaytow","sequence":"first","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences, University of Edinburgh , Edinburgh EH8 9AG , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7633-4790","authenticated-orcid":false,"given":"Anna A L","family":"Motyl","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences, University of Edinburgh , Edinburgh EH8 9AG , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences, University of Edinburgh , Edinburgh EH8 9AG , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8488-037X","authenticated-orcid":false,"given":"Charis","family":"Wong","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB , UK"},{"name":"Anne Rowling Regenerative Neurology Clinic, University of Edinburgh , Edinburgh EH16 4SB , UK"},{"name":"MRC Clinical Trials Unit, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian L","family":"Currie","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsanett","family":"Bahor","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3282-8502","authenticated-orcid":false,"given":"Emily","family":"Sena","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0306-5577","authenticated-orcid":false,"given":"Thomas H","family":"Gillingwater","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences, University of Edinburgh , Edinburgh EH8 9AG , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease, University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"issue":"1","key":"2024082311411849900_fcae267-B1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ejhg.2011.134","article-title":"Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of &gt;72 400 specimens","volume":"20","author":"Sugarman","year":"2012","journal-title":"Eur J Hum Genet"},{"issue":"3","key":"2024082311411849900_fcae267-B2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/joa.12419","article-title":"Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy","volume":"228","author":"Powis","year":"2016","journal-title":"J Anat"},{"issue":"1","key":"2024082311411849900_fcae267-B3","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"},{"issue":"11","key":"2024082311411849900_fcae267-B4","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","article-title":"A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy","volume":"96","author":"Lorson","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"2024082311411849900_fcae267-B5","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":"2024082311411849900_fcae267-B6","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13023-017-0671-8","article-title":"Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy\u2014A literature review","volume":"12","author":"Verhaart","year":"2017","journal-title":"Orphanet J Rare Dis"},{"issue":"20","key":"2024082311411849900_fcae267-B7","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1212\/01.wnl.0000290830.40544.b9","article-title":"The changing natural history of spinal muscular atrophy type 1","volume":"69","author":"Oskoui","year":"2007","journal-title":"Neurology"},{"key":"2024082311411849900_fcae267-B8","doi-asserted-by":"crossref","first-page":"100346","DOI":"10.1016\/j.xcrm.2021.100346","article-title":"Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine","volume":"2","author":"Chaytow","year":"2021","journal-title":"Cell Rep Med"},{"key":"2024082311411849900_fcae267-B9","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.2147\/TCRM.S172291","article-title":"Clinical evidence supporting early treatment of patients with spinal muscular atrophy: Current perspectives","volume":"15","author":"Dangouloff","year":"2019","journal-title":"Ther Clin Risk Manag"},{"key":"2024082311411849900_fcae267-B10","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1007\/s12035-017-0831-9","article-title":"Time is motor neuron: Therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy","volume":"55","author":"Govoni","year":"2018","journal-title":"Mol Neurobiol"},{"issue":"11","key":"2024082311411849900_fcae267-B11","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.nmd.2019.09.007","article-title":"Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the phase 2 NURTURE study","volume":"29","author":"De Vivo","year":"2019","journal-title":"Neuromuscul Disord."},{"key":"2024082311411849900_fcae267-B12","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1038\/s41591-022-01866-4","article-title":"Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: The phase III SPR1NT trial","volume":"28","author":"Strauss","year":"2022","journal-title":"Nat Med"},{"key":"2024082311411849900_fcae267-B13","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1038\/s41591-022-01867-3","article-title":"Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: The phase III SPR1NT trial","volume":"28","author":"Strauss","year":"2022","journal-title":"Nat Med"},{"key":"2024082311411849900_fcae267-B14","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s40258-020-00624-2","article-title":"Costs of illness of spinal muscular atrophy: A systematic review","volume":"19","author":"Landfeldt","year":"2021","journal-title":"Appl Health Econ Health Policy"},{"key":"2024082311411849900_fcae267-B15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13023-021-01695-7","article-title":"Systematic literature review of the economic burden of spinal muscular atrophy and economic evaluations of treatments","volume":"16","author":"Dangouloff","year":"2021","journal-title":"Orphanet J Rare Dis"},{"issue":"6","key":"2024082311411849900_fcae267-B16","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.nmd.2021.03.007","article-title":"Newborn screening programs for spinal muscular atrophy worldwide: Where we stand and where to go","volume":"31","author":"Dangouloff","year":"2021","journal-title":"Neuromuscul Disord"},{"key":"2024082311411849900_fcae267-B17","doi-asserted-by":"crossref","first-page":"e3001177","DOI":"10.1371\/journal.pbio.3001177","article-title":"Epidemiology and reporting characteristics of preclinical systematic reviews","volume":"19","author":"Hunniford","year":"2021","journal-title":"PLoS Biol"},{"issue":"1","key":"2024082311411849900_fcae267-B18","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12915-023-01686-z","article-title":"The automated systematic search deduplicator (ASySD): A rapid, open-source, interoperable tool to remove duplicate citations in biomedical systematic review","volume":"21","author":"Hair","year":"2023","journal-title":"BMC Biol"},{"issue":"1","key":"2024082311411849900_fcae267-B19","doi-asserted-by":"crossref","first-page":"100103","DOI":"10.1136\/bmjos-2020-100103","article-title":"Development and uptake of an online systematic review platform: The early years of the CAMARADES systematic review facility (SyRF)","volume":"5","author":"Bahor","year":"2021","journal-title":"BMJ Open Sci"},{"key":"2024082311411849900_fcae267-B20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1471-2288-14-43","article-title":"SYRCLE\u2019s risk of bias tool for animal studies","volume":"14","author":"Hooijmans","year":"2014","journal-title":"BMC Med Res Methodol"},{"issue":"1","key":"2024082311411849900_fcae267-B21","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/bjc.2012.504","article-title":"Systematic review and meta-analysis of temozolomide in animal models of glioma: Was clinical efficacy predicted?","volume":"108","author":"Hirst","year":"2013","journal-title":"Br J Cancer"},{"key":"2024082311411849900_fcae267-B22","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jneumeth.2013.09.010","article-title":"Meta-analysis of data from animal studies: A practical guide","volume":"221","author":"Vesterinen","year":"2014","journal-title":"J Neurosci Methods"},{"issue":"3","key":"2024082311411849900_fcae267-B23","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1161\/STROKEAHA.107.498725","article-title":"Empirical evidence of bias in the design of experimental stroke studies: A metaepidemiologic approach","volume":"39","author":"Crossley","year":"2008","journal-title":"Stroke"},{"key":"2024082311411849900_fcae267-B24","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1111\/bph.15193","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"177","author":"Percie du Sert","year":"2020","journal-title":"Br J Pharmacol"},{"key":"2024082311411849900_fcae267-B25","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41684-020-0641-y","article-title":"Arriving again: 10 years on, ARRIVE 2.0 offers a simplified set of reporting guidelines","volume":"49","author":"Katsnelson","year":"2020","journal-title":"Lab Anim (NY)"},{"key":"2024082311411849900_fcae267-B26","doi-asserted-by":"crossref","first-page":"100725","DOI":"10.1016\/j.xcrm.2022.100725","article-title":"Timing is everything: Clinical evidence supports pre-symptomatic treatment for spinal muscular atrophy","volume":"3","author":"Motyl","year":"2022","journal-title":"Cell Rep Med"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcae267\/58800544\/fcae267.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/6\/4\/fcae267\/58902592\/fcae267.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/6\/4\/fcae267\/58902592\/fcae267.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T23:31:58Z","timestamp":1724455918000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcae267\/7731785"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024]]},"references-count":26,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,7,2]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcae267","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024]]},"published":{"date-parts":[[2024]]},"article-number":"fcae267"}}