{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:11:55Z","timestamp":1788862315871,"version":"build-2803163510"},"reference-count":128,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Since its discovery in the late 19th century, spinal muscular atrophy (SMA) has had a significant medical and societal impact, primarily affecting newborns, toddlers, and young adults. While new pharmaceutical strategies are effective in treating SMA in a particular subset of patients, continued research is necessary to improve the well-being of patients. Treatments are needed for those who do not respond to newly approved drugs and older patients with significantly compromised neuron systems. After summarizing SMA genotypes, phenotypes, and approved pharmacological treatments, this review presents ongoing trials for approved and new molecules, new formulations, and administration methods. Based on the work of our lab, we also discuss nutritional interventions that aim to counteract the oxidative stress present in SMA cells. Finally, we assess rehabilitative interventions, focusing on psychological approaches.<\/jats:p>","DOI":"10.3390\/biology14080977","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Managing Spinal Muscular Atrophy: A Look at the Biology and Treatment Strategies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8693-6330","authenticated-orcid":false,"given":"Arianna","family":"Vezzoli","sequence":"first","affiliation":[{"name":"Department of Pharmacological Science, University of Milan, Via G. Balzaretti 9, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7951-9512","authenticated-orcid":false,"given":"Daniele","family":"Bottai","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Science, University of Milan, Via G. Balzaretti 9, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9656-3219","authenticated-orcid":false,"given":"Raffaella","family":"Adami","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Science, University of Milan, Via G. Balzaretti 9, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hu, C., Li, X., Shi, Y., Zhu, X., Zhao, L., Li, W., Zhou, S., and Wang, Y. (2022). Comprehensive profile and natural history of pediatric patients with spinal muscular atrophy: A large retrospective study from China. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.1038012"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s12015-019-09910-6","article-title":"Spinal Muscular Atrophy Modeling and Treatment Advances by Induced Pluripotent Stem Cells Studies","volume":"15","author":"Adami","year":"2019","journal-title":"Stem. Cell. Rev. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"fcaa075","DOI":"10.1093\/braincomms\/fcaa075","article-title":"Intragenic and structural variation in the","volume":"2","author":"Wadman","year":"2020","journal-title":"Brain Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/344767a0","article-title":"Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q","volume":"344","author":"Melki","year":"1990","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/344540a0","article-title":"Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3","volume":"344","author":"Brzustowicz","year":"1990","journal-title":"Nature"},{"key":"ref_6","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":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/ng0797-265","article-title":"Correlation between severity and SMN protein level in spinal muscular atrophy","volume":"16","author":"Lefebvre","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bbagrm.2016.12.008","article-title":"Diverse role of survival motor neuron protein","volume":"1860","author":"Singh","year":"2017","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref_9","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 >72,400 specimens","volume":"20","author":"Sugarman","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). GeneReviews, University of Washington."},{"key":"ref_11","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."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Boemer, F., Caberg, J.H., Beckers, P., Dideberg, V., di Fiore, S., Bours, V., Marie, S., Dewulf, J., Marcelis, L., and Deconinck, N. (2021). Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-99496-2"},{"key":"ref_13","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":"ref_14","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1136\/jnnp-2021-326344","article-title":"Newborn screening for spinal muscular atrophy with disease-modifying therapies: A cost-effectiveness analysis","volume":"92","author":"Shih","year":"2021","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zaidman, C.M., Crockett, C.D., Wedge, E., Tabatabai, G., and Goedeker, N. (2024). Newborn Screening for Spinal Muscular Atrophy: Variations in Practice and Early Management of Infants with Spinal Muscular Atrophy in the United States. Int. J. Neonatal. Screen., 10.","DOI":"10.3390\/ijns10030058"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1080\/1028415X.2020.1760531","article-title":"Curcumin and neurological diseases","volume":"25","author":"Adami","year":"2022","journal-title":"Nutr. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2147\/TACG.S239603","article-title":"Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance","volume":"14","author":"Keinath","year":"2021","journal-title":"Appl. Clin. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Adami, R., and Bottai, D. (2022). NSC Physiological Features in Spinal Muscular Atrophy: SMN Deficiency Effects on Neurogenesis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315209"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/BF00314486","article-title":"A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya","volume":"235","author":"Radhakrishnan","year":"1988","journal-title":"J. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0022-510X(01)00574-3","article-title":"Molecular analysis of SMN, NAIP and P44 genes of SMA patients and their families","volume":"190","author":"Tsai","year":"2001","journal-title":"J. Neurol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00439-019-01983-0","article-title":"Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype","volume":"138","author":"Ruhno","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000022909","article-title":"Analysis of the SMN and NAIP genes in slovak spinal muscular atrophy patients","volume":"50","author":"Hahnen","year":"2000","journal-title":"Hum. Hered."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1002\/j.1460-2075.1996.tb00725.x","article-title":"A novel nuclear structure containing the survival of motor neurons protein","volume":"15","author":"Liu","year":"1996","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/S0092-8674(00)80367-0","article-title":"The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins","volume":"90","author":"Liu","year":"1997","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.brainres.2012.01.044","article-title":"Spinal muscular atrophy: The role of SMN in axonal mRNA regulation","volume":"1462","author":"Fallini","year":"2012","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/hmg\/11.1.93","article-title":"Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp\/hnRNP-Q: A role for Smn in RNA processing in motor axons?","volume":"11","author":"Rossoll","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s12031-007-0024-5","article-title":"Smn depletion alters profilin II expression and leads to upregulation of the RhoA\/ROCK pathway and defects in neuronal integrity","volume":"32","author":"Bowerman","year":"2007","journal-title":"J. Mol. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e70055","DOI":"10.1096\/fj.202300183R","article-title":"The spinal muscular atrophy gene product regulates actin dynamics","volume":"38","author":"Zeug","year":"2024","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Faravelli, I., Riboldi, G.M., Rinchetti, P., and Lotti, F. (2023). The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032247"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.yexcr.2004.03.022","article-title":"The SMN complex","volume":"296","author":"Gubitz","year":"2004","journal-title":"Exp. Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/3030","article-title":"Differential SMN2 expression associated with SMA severity","volume":"20","author":"Gavrilov","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_32","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":"ref_33","doi-asserted-by":"crossref","unstructured":"O\u2019Hern, P., Garcia, E.L., Hao, L.T., \u00f9Hart, A.C., Matera, A.G., and Beattie, C.E. (2017). Nonmammalian Animal Models of Spinal Muscular Atrophy, Academic Press.","DOI":"10.1016\/B978-0-12-803685-3.00014-8"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0378-1119(01)00758-2","article-title":"The SMN genes are subject to transcriptional regulation during cellular differentiation","volume":"279","author":"Brun","year":"2001","journal-title":"Gene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1146\/annurev-genom-102319-103602","article-title":"Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next","volume":"21","author":"Wirth","year":"2020","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1007\/s13311-014-0314-x","article-title":"The Genetics of Spinal Muscular Atrophy: Progress and Challenges","volume":"12","author":"Farrar","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00439-008-0598-1","article-title":"Mutation update of spinal muscular atrophy in Spain: Molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene","volume":"125","author":"Bernal","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/ng1195-335","article-title":"A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients","volume":"11","author":"Bussaglia","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.nmd.2014.04.003","article-title":"Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients","volume":"24","author":"Gos","year":"2014","journal-title":"Neuromuscul. Disord."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9","article-title":"An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)","volume":"15","author":"Wirth","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_41","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":"Schwarzer","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1086\/301608","article-title":"De novo rearrangements found in 2% of index patients with spinal muscular atrophy: Mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling","volume":"61","author":"Wirth","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Aasdev, A., Sreelekshmi, R.S., Iyer, V.R., and Moharir, S.C. (2024). Spinal muscular atrophy: Molecular mechanism of pathogenesis, diagnosis, therapeutics, and clinical trials in the Indian context. J. Biosci., 49.","DOI":"10.1007\/s12038-023-00412-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ogc.2017.02.004","article-title":"Prenatal Diagnosis: Screening and Diagnostic Tools","volume":"44","author":"Carlson","year":"2017","journal-title":"Obstet. Gynecol. Clin. North Am."},{"key":"ref_45","first-page":"CD003252","article-title":"Amniocentesis and chorionic villus sampling for prenatal diagnosis","volume":"9","author":"Alfirevic","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1007\/s00018-018-2849-1","article-title":"The role of survival motor neuron protein (SMN) in protein homeostasis","volume":"75","author":"Chaytow","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/bpa.12071","article-title":"Spinal muscular atrophy: New findings for an old pathology","volume":"23","author":"Bottai","year":"2013","journal-title":"Brain Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00415-024-12724-3","article-title":"Cytoskeleton dysfunction of motor neuron in spinal muscular atrophy","volume":"272","author":"Shi","year":"2024","journal-title":"J. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1093\/hmg\/ddab220","article-title":"SMN protein is required throughout life to prevent spinal muscular atrophy disease progression","volume":"31","author":"Zhao","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.nmd.2017.11.005","article-title":"Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care","volume":"28","author":"Mercuri","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/gt.2017.52","article-title":"The clinical landscape for SMA in a new therapeutic era","volume":"24","author":"Talbot","year":"2017","journal-title":"Gene. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ejpn.2024.06.001","article-title":"2024 update: European consensus statement on gene therapy for spinal muscular atrophy","volume":"51","author":"Kirschner","year":"2024","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_53","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. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1750-1172-6-71","article-title":"Spinal muscular atrophy","volume":"6","author":"Mercuri","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1090-3798(99)80012-9","article-title":"Very severe spinal muscular atrophy (SMA type 0): An expanding clinical phenotype","volume":"3","author":"Dubowitz","year":"1999","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/mus.24497","article-title":"Spinal muscular atrophy: Diagnosis and management in a new therapeutic era","volume":"51","author":"Arnold","year":"2015","journal-title":"Muscle Nerve"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Corsello, A., Scatigno, L., Pascuzzi, M.C., Calcaterra, V., Dilillo, D., Vizzuso, S., Pelizzo, G., Zoia, E., Mandelli, A., and Govoni, A. (2021). Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1. Nutrients, 13.","DOI":"10.20944\/preprints202106.0184.v1"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1242\/dmm.007245","article-title":"The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy","volume":"4","author":"Sleigh","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"ref_59","first-page":"175","article-title":"Cardiac involvement in patients with spinal muscular atrophies","volume":"30","author":"Palladino","year":"2011","journal-title":"Acta Myol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jpeds.2009.01.071","article-title":"Vascular perfusion abnormalities in infants with spinal muscular atrophy","volume":"155","author":"Araujo","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/mus.21654","article-title":"Digital necroses and vascular thrombosis in severe spinal muscular atrophy","volume":"42","author":"Vogelgesang","year":"2010","journal-title":"Muscle Nerve"},{"key":"ref_62","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":"ref_63","doi-asserted-by":"crossref","unstructured":"K\u00f6lbel, H., Hauffa, B.P., Wudy, S.A., Bouikidis, A., Della Marina, A., and Schara, U. (2017). Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175611"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Butchbach, M.E.R. (2021). Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157896"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"656","DOI":"10.58600\/eurjther1516","article-title":"Rehabilitation in Spinal Muscular Atrophy; A Narrative Review","volume":"29","author":"Agyenkwa","year":"2023","journal-title":"Eur. J. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.pediatrneurol.2015.06.002","article-title":"Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review","volume":"53","author":"Lin","year":"2015","journal-title":"Pediatr. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Varone, A., Esposito, G., and Bitetti, I. (2025). Spinal muscular atrophy in the era of newborn screening: How the classification could change. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1542396"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Cantara, S., Simoncelli, G., and Ricci, C. (2024). Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202402.1738.v1"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s12276-022-00757-5","article-title":"RNA therapy: Rich history, various applications and unlimited future prospects","volume":"54","author":"Kim","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Messina, S., and Sframeli, M. (2020). New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges. J. Clin. Med., 9.","DOI":"10.3390\/jcm9072222"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nn.4508","article-title":"Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy","volume":"20","author":"Corey","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Cort\u00e9s, A., Echeverr\u00eda-Garc\u00e9s, G., and Ramos-Medina, M.J. (2022). Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy. Biology, 11.","DOI":"10.3390\/biology11060894"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5378","DOI":"10.1007\/s00415-024-12442-w","article-title":"Nusinersen effectiveness and safety in pediatric patients with 5q-spinal muscular atrophy: A multi-center disease registry in China","volume":"271","author":"Yao","year":"2024","journal-title":"J. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1212\/CPJ.0000000000000718","article-title":"A multidisciplinary approach to dosing nusinersen for spinal muscular atrophy","volume":"9","author":"Zingariello","year":"2019","journal-title":"Neurol. Clin. Pract."},{"key":"ref_75","first-page":"194","article-title":"Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy","volume":"24","author":"Neil","year":"2019","journal-title":"J. Pediatr. Pharmacol. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1002\/mus.27187","article-title":"Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study","volume":"63","author":"Acsadi","year":"2021","journal-title":"Muscle Nerve"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/mus.27853","article-title":"Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study","volume":"68","author":"Crawford","year":"2023","journal-title":"Muscle Nerve"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"100862","DOI":"10.1016\/j.lanepe.2024.100862","article-title":"Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: A prospective European multinational observational study","volume":"39","author":"Wurster","year":"2024","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1590\/s1679-45082017rb4024","article-title":"Gene therapy: Advances, challenges and perspectives","volume":"15","author":"Paiva","year":"2017","journal-title":"Einstein"},{"key":"ref_80","first-page":"e36197","article-title":"Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma)","volume":"15","author":"Ogbonmide","year":"2023","journal-title":"Cureus"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"100817","DOI":"10.1016\/j.lanepe.2023.100817","article-title":"Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: Real-world evidence from 6 infusion centres in the United Kingdom","volume":"37","author":"Gowda","year":"2024","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/13543784.2022.2056836","article-title":"Risdiplam: An investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)","volume":"31","author":"Markati","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_83","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":"ref_84","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1021\/acsmedchemlett.0c00659","article-title":"Risdiplam, the First Approved Small Molecule Splicing Modifier Drug as a Blueprint for Future Transformative Medicines","volume":"12","author":"Ratni","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/S1474-4422(22)00339-8","article-title":"Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): Secondary analyses from an open-label trial","volume":"21","author":"Masson","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2217\/cer-2021-0216","article-title":"How does risdiplam compare with other treatments for Types 1\u20133 spinal muscular atrophy: A systematic literature review and indirect treatment comparison","volume":"11","author":"Ribero","year":"2022","journal-title":"J. Comp. Eff. Res."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Belan\u010di\u0107, A., Strbad, T., Ku\u010dan \u0160tigli\u0107, M., and Vitezi\u0107, D. (2024). Switching from Nusinersen to Risdiplam: A Croatian Real-World Experience on Effectiveness and Safety. J. Pers. Med., 14.","DOI":"10.20944\/preprints202311.1564.v1"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1056\/NEJMc2300802","article-title":"Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy","volume":"392","author":"Finkel","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"eadv4656","DOI":"10.1126\/scitranslmed.adv4656","article-title":"Intra-amniotic antisense oligonucleotide treatment improves phenotypes in preclinical models of spinal muscular atrophy","volume":"17","author":"Borges","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Crawford, T.O., Day, J.W., De Vivo, D.C., Krueger, J.M., Mercuri, E., Nascimento, A., Pasternak, A., Mazzone, E.S., Duong, T., and Song, G. (2024). Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: Results from the 36-month TOPAZ study. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1419791"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e209151","DOI":"10.1212\/WNL.0000000000209151","article-title":"Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study","volume":"102","author":"Crawford","year":"2024","journal-title":"Neurology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/10915818211025477","article-title":"Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease","volume":"40","author":"Welsh","year":"2021","journal-title":"Int. J. Toxicol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Singh, A., Kukreti, R., Saso, L., and Kukreti, S. (2019). Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules, 24.","DOI":"10.3390\/molecules24081583"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Singh, N.N., Seo, J., Rahn, S.J., and Singh, R.N. (2012). A multi-exon-skipping detection assay reveals surprising diversity of splice isoforms of spinal muscular atrophy genes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049595"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Seo, J., Singh, N.N., Ottesen, E.W., Sivanesan, S., Shishimorova, M., and Singh, R.N. (2016). Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154390"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Adami, R., Pezzotta, M., Cadile, F., Cuniolo, B., Rovati, G., Canepari, M., and Bottai, D. (2024). Physiological Features of the Neural Stem Cells Obtained from an Animal Model of Spinal Muscular Atrophy and Their Response to Antioxidant Curcumin. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158364"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Chen, M.M., Zhao, Y.P., Zhao, Y., Deng, S.L., and Yu, K. (2021). Regulation of Myostatin on the Growth and Development of Skeletal Muscle. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.785712"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1007\/s00018-022-04408-w","article-title":"Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases","volume":"79","author":"Abati","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Servais, L., Lair, L.L., Connolly, A.M., Byrne, B.J., Chen, K.S., Coric, V., Qureshi, I., Durham, S., Campbell, D.J., and Maclaine, G. (2024). Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910273"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Chen, T.H. (2020). New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093297"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Liu, M., Hammers, D.W., Barton, E.R., and Sweeney, H.L. (2016). Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166803"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1093\/hmg\/ddx124","article-title":"Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice","volume":"26","author":"Kim","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1007\/s00431-023-04883-8","article-title":"New therapies for spinal muscular atrophy: Where we stand and what is next","volume":"182","author":"Antonaci","year":"2023","journal-title":"Eur. J. Pediatr."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"100826","DOI":"10.1016\/j.isci.2020.100826","article-title":"R-Roscovitine Improves Motoneuron Function in Mouse Models for Spinal Muscular Atrophy","volume":"23","author":"Tejero","year":"2020","journal-title":"iScience"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.omtm.2018.01.007","article-title":"Plastin 3 Promotes Motor Neuron Axonal Growth and Extends Survival in a Mouse Model of Spinal Muscular Atrophy","volume":"9","author":"Alrafiah","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1080\/14789450.2017.1345631","article-title":"Advances in understanding the role of disease-associated proteins in spinal muscular atrophy","volume":"14","author":"Hosseinibarkooie","year":"2017","journal-title":"Expert Rev. Proteom."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e2216814120","DOI":"10.1073\/pnas.2216814120","article-title":"Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice","volume":"120","author":"Boido","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.nmd.2019.04.003","article-title":"Salbutamol tolerability and efficacy in patients with spinal muscular atrophy type II","volume":"29","author":"Frongia","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/mus.26823","article-title":"Evaluation of body composition as a potential biomarker in spinal muscular atrophy","volume":"61","author":"Baranello","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Deguise, M.O., Chehade, L., and Kothary, R. (2021). Metabolic Dysfunction in Spinal Muscular Atrophy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115913"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Li, Y.J., Chen, T.H., Wu, Y.Z., and Tseng, Y.H. (2020). Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy. Nutrients, 12.","DOI":"10.3390\/nu12123842"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1016\/j.jpedsurg.2008.05.035","article-title":"Early laparoscopic fundoplication and gastrostomy in infants with spinal muscular atrophy type I","volume":"43","author":"Durkin","year":"2008","journal-title":"J. Pediatr. Surg."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.nutos.2023.12.005","article-title":"Nutritional status and dietary intake in children and adolescents with spinal muscular atrophy types II and III on treatment with nusinersen","volume":"53","author":"Vetlesen","year":"2024","journal-title":"Clin. Nutr. Open Sci."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Kant-Smits, K., Bartels, B., Asselman, F.L., Veldhoen, E.S., van Eijk, R.P.A., van der Pol, W.L., and Hulzebos, E.H.J. (2023). The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): Study protocol for a randomized controlled trial. BMC Neurol., 23.","DOI":"10.1186\/s12883-023-03136-3"},{"key":"ref_115","first-page":"CD012120","article-title":"Physical exercise training for type 3 spinal muscular atrophy","volume":"3","author":"Bartels","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/mus.24568","article-title":"Resistance strength training exercise in children with spinal muscular atrophy","volume":"52","author":"Lewelt","year":"2015","journal-title":"Muscle Nerve"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Belli, S., Prince, I., Savio, G., Paracchini, E., Cattaneo, D., Bianchi, M., Masocco, F., Bellanti, M.T., and Balbi, B. (2021). Airway Clearance Techniques: The Right Choice for the Right Patient. Front. Med., 8.","DOI":"10.3389\/fmed.2021.544826"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.rmed.2018.01.012","article-title":"Airway clearance techniques in neuromuscular disorders: A state of the art review","volume":"136","author":"Chatwin","year":"2018","journal-title":"Respir. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ejpn.2022.12.006","article-title":"Behavioral problems in infants and young children with spinal muscular atrophy and their siblings: A cross-sectional study","volume":"42","author":"Panda","year":"2023","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1186\/s13023-021-02008-8","article-title":"Anxiety and depression in school-age patients with spinal muscular atrophy: A cross-sectional study","volume":"16","author":"Yao","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"366","DOI":"10.5152\/TurkArchPediatr.2021.20117","article-title":"The Burden of Primary Caregivers of Spinal Muscular Atrophy Patients and Their Needs","volume":"56","author":"Ergenekon","year":"2021","journal-title":"Turk. Arch. Pediatr."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Inhestern, L., Brandt, M., Driemeyer, J., Denecke, J., Johannsen, J., and Bergelt, C. (2023). Experiences of Health Care and Psychosocial Needs in Parents of Children with Spinal Muscular Atrophy. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20075360"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3233\/JND-160177","article-title":"Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients","volume":"3","author":"Grotto","year":"2016","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.nmd.2017.09.015","article-title":"Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy","volume":"28","author":"Pane","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1469-8749.2003.tb00858.x","article-title":"Behavioural problems in children and adolescents with spinal muscular atrophy and their siblings","volume":"45","author":"Zerres","year":"2003","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12671-020-01500-9","article-title":"The Effectiveness of Mindfulness-Based Stress Reduction on the Psychological Functioning of Healthcare Professionals: A Systematic Review","volume":"12","author":"Kriakous","year":"2021","journal-title":"Mindfulness"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s13023-022-02351-4","article-title":"A mixed method study on the impact of living with spinal muscular atrophy in Malaysia from patients\u2019 and caregivers\u2019 perspectives","volume":"17","author":"Koh","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e200310","DOI":"10.1212\/CPJ.0000000000200310","article-title":"Spinal Muscular Atrophy Update in Best Practices: Recommendations for Diagnosis Considerations","volume":"14","author":"Schroth","year":"2024","journal-title":"Neurol. Clin. Pract."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/8\/977\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:07Z","timestamp":1760034067000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/8\/977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,1]]},"references-count":128,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["biology14080977"],"URL":"https:\/\/doi.org\/10.3390\/biology14080977","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,1]]}}}