{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T21:36:06Z","timestamp":1793050566189,"version":"4.5.0"},"reference-count":99,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biohaven Pharmaceuticals, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-\u03b2 superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.<\/jats:p>","DOI":"10.3390\/ijms251910273","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T10:41:47Z","timestamp":1727174507000},"page":"10273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9270-4061","authenticated-orcid":false,"given":"Laurent","family":"Servais","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Division of Child Neurology, Department of Paediatrics, Centre de R\u00e9f\u00e9rence des Maladies Neuromusculaires, University Hospital of Li\u00e8ge, University of Li\u00e8ge, Boulevard Du 12e De Ligne, 4000 Liege, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5961-482X","authenticated-orcid":false,"given":"Lindsey Lee","family":"Lair","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Connolly","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry J.","family":"Byrne","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen S.","family":"Chen","sequence":"additional","affiliation":[{"name":"Spinal Muscular Atrophy Foundation, 970 W Broadway STE E, PMB 140, Jackson, WY 83001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad","family":"Coric","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irfan","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Durham","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Maclaine","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackie","family":"Marin","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford","family":"Bechtold","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Aragon-Gawinska, K., Mouraux, C., Dangouloff, T., and Servais, L. (2023). Spinal Muscular Atrophy Treatment in Patients Identified by Newborn Screening\u2014A Systematic Review. Genes, 14.","DOI":"10.3390\/genes14071377"},{"key":"ref_2","unstructured":"Burr, P., and Reddivari, A.K.R. (2024, May 14). National Library of Medicine, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK560687\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41572-022-00380-8","article-title":"Spinal muscular atrophy","volume":"8","author":"Mercuri","year":"2022","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.nmd.2018.01.003","article-title":"Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases","volume":"28","author":"Calucho","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S163","DOI":"10.1016\/j.nmd.2023.07.381","article-title":"P04 Taldefgrobep alfa: Preclinical and clinical data supporting the phase 3 RESILIENT study in spinal muscular atrophy","volume":"33","author":"Lair","year":"2023","journal-title":"Neuromuscul. Disord."},{"key":"ref_6","unstructured":"(2024, May 30). Cure SMA. Available online: https:\/\/www.curesma.org\/testing-diagnosis\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/acn3.51281","article-title":"Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study","volume":"8","author":"Annoussamy","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1212\/CON.0000000000001338","article-title":"Spinal Muscular Atrophy","volume":"29","author":"Oskoui","year":"2023","journal-title":"Contin. Lifelong Learn. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_10","unstructured":"(2024, May 30). Spinraza. Available online: https:\/\/www.spinraza.com\/content\/dam\/commercial\/spinraza\/caregiver\/en_us\/pdf\/spinraza-prescribing-information.pdf."},{"key":"ref_11","unstructured":"(2024, May 30). Novartis. Available online: https:\/\/www.novartis.com\/us-en\/sites\/novartis_us\/files\/zolgensma.pdf."},{"key":"ref_12","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":"ref_13","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1056\/NEJMoa2102047","article-title":"Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls","volume":"385","author":"Darras","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_14","unstructured":"(2024, June 05). Genentech. Available online: https:\/\/www.gene.com\/download\/pdf\/evrysdi_prescribing.pdf."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/S1474-4422(21)00367-7","article-title":"Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial","volume":"21","author":"Mercuri","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1001\/jamaneurol.2021.1272","article-title":"Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy","volume":"78","author":"Mendell","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S1474-4422(21)00001-6","article-title":"Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): An open-label, single-arm, multicentre, phase 3 trial","volume":"20","author":"Day","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1186\/s13023-021-02065-z","article-title":"Motor function in type 2 and 3 SMA patients treated with Nusinersen: A critical review and meta-analysis","volume":"16","author":"Coratti","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1056\/NEJMoa1710504","article-title":"Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy","volume":"378","author":"Mercuri","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1016\/S0140-6736(16)31408-8","article-title":"Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study","volume":"388","author":"Finkel","year":"2016","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1111\/ene.15499","article-title":"Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment","volume":"30","author":"Mercuri","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JND-190424","article-title":"Advances in Treatment of Spinal Muscular Atrophy\u2014New Phenotypes, New Challenges, New Implications for Care","volume":"7","author":"Schorling","year":"2020","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","unstructured":"Day, J.W., Howell, K., Place, A., Long, K., Rossello, J., Kertesz, N., and Nomikos, G. (2022). Advances and limitations for the treatment of spinal muscular atrophy. BMC Pediatr., 22.","DOI":"10.1186\/s12887-022-03671-x"},{"key":"ref_25","unstructured":"(2023, May 31). Cure SMA. Available online: https:\/\/www.curesma.org\/wp-content\/uploads\/2022\/08\/NIH_SMA_Research_FactSheet_vFnl.pdf."},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s13311-022-01200-3","article-title":"Nusinersen in Adults with 5q Spinal Muscular Atrophy: A Systematic Review and Meta-analysis","volume":"19","author":"Gavriilaki","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1056\/NEJMoa040933","article-title":"Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child","volume":"350","author":"Schuelke","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","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_30","doi-asserted-by":"crossref","first-page":"12457","DOI":"10.1073\/pnas.94.23.12457","article-title":"Double muscling in cattle due to mutations in the myostatin gene","volume":"94","author":"McPherron","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","unstructured":"(2024, May 30). National Library of Medicine, Available online: https:\/\/medlineplus.gov\/genetics\/gene\/mstn\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/387083a0","article-title":"Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member","volume":"387","author":"McPherron","year":"1997","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2021.04.001","article-title":"Principles of the activin receptor signaling pathway and its inhibition","volume":"60","author":"Lodberg","year":"2021","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_34","unstructured":"Zaidi, M. (2020). Current and Emerging Bone-Targeted Therapies for the Treatment of Bone Metastases from Solid Tumors. Encyclopedia of Bone Biology, Elsevier. [1st ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/bs.acc.2021.09.006","article-title":"Myostatin: Basic biology to clinical application","volume":"Volume 106","author":"Makowski","year":"2022","journal-title":"Advances in Clinical Chemistry"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Baig, M.H., Ahmad, K., Moon, J.S., Park, S.-Y., Lim, J.H., Chun, H.J., Qadri, A.F., Hwang, Y.C., Jan, A.T., and Ahmad, S.S. (2022). Myostatin and its Regulation: A Comprehensive Review of Myostatin Inhibiting Strategies. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.876078"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41467-017-01486-4","article-title":"Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches","volume":"8","author":"Mariot","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1210\/endrev\/bnab030","article-title":"Myostatin\/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs","volume":"43","author":"Rodgers","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/mus.27558","article-title":"Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy","volume":"66","author":"Statland","year":"2022","journal-title":"Muscle Nerve"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/ana.21338","article-title":"A phase I\/IItrial of MYO-029 in adult subjects with muscular dystrophy","volume":"63","author":"Wagner","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s40120-023-00570-w","article-title":"The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy","volume":"13","author":"Muntoni","year":"2024","journal-title":"Neurol. Ther."},{"key":"ref_42","unstructured":"(2024, May 30). National Library of Medicine, Available online: https:\/\/clinicaltrials.gov\/study\/NCT03710941."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jha, N.N., Kim, J.-K., Her, Y.-R., and Monani, U.R. (2023). Muscle: To the neuromuscular disease phenotype in spinal muscular atrophy. J. Clin. Investig., 8.","DOI":"10.1172\/jci.insight.171878"},{"key":"ref_44","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":"ref_45","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.ydbio.2012.05.037","article-title":"A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein","volume":"368","author":"Hayhurst","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1093\/hmg\/ddy382","article-title":"Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy","volume":"28","author":"Long","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Mackels, L., Mariot, V., Buscemi, L., Servais, L., and Dumonceaux, J. (2024). Impact of Disease Severity and Disease-Modifying Therapies on Myostatin Levels in SMA Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168763"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1002\/jcsm.12542","article-title":"Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy","volume":"11","author":"Zhou","year":"2020","journal-title":"J. Cachex-Sarcopenia Muscle"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Nielsen, T.L., Vissing, J., and Krag, T.O. (2021). Antimyostatin Treatment in Health and Disease: The Story of Great Expectations and Limited Success. Cells, 10.","DOI":"10.3390\/cells10030533"},{"key":"ref_50","unstructured":"(2024, June 06). ScienceDirect. Available online: https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/activin-receptor-1."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.1212\/WNL.0000000000205020","article-title":"The Phase 3 RESILIENT Study: Taldefgrobep Alfa in Spinal Muscular Atrophy (P2-11.008)","volume":"102","author":"Lair","year":"2024","journal-title":"Neurology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15153","DOI":"10.1038\/ncomms15153","article-title":"Activin A more prominently regulates muscle mass in primates than does GDF8","volume":"8","author":"Latres","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_53","unstructured":"(2024, May 30). National Library of Medicine, Available online: https:\/\/clinicaltrials.gov\/study\/NCT03100630."},{"key":"ref_54","unstructured":"(2024, May 30). National Library of Medicine, Available online: https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT02145234."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Lair, L., Qureshi, I., Bechtold, C., Heller, L., Durham, S., Campbell, D., Marin, J., Chen, K., and Coric, V.I. (2024, January 16). Taldefgrobep alfa Preclinical and Clinical Data Supporting the Phase 3 RESILIENT Study in SMA. Proceedings of the 4th Scientific International Congress of Spinal Muscular Atrophy, Ghent, Belgium.","DOI":"10.1016\/j.nmd.2023.07.381"},{"key":"ref_56","unstructured":"(2023, December 31). National Library of Medicine, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05337553."},{"key":"ref_57","unstructured":"(2024, June 06). Biohaven, Ltd. Available online: https:\/\/ir.biohaven.com\/news-releases\/news-release-details\/biohaven-completes-enrollment-pivotal-phase-3-study-taldefgrobep\/."},{"key":"ref_58","unstructured":"Lair, L., Qureshi, I., Bechtold, C., Durham, S., Campbell, D., Marin, J., and Coric, V. (2023, January 14). The Phase 3 RESILIENT Study in Spinal Muscular Atrophy. Proceedings of the 9th Congress of the European Academy of Neurology, Budapest, Hungary."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S1474-4422(17)30085-6","article-title":"Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: A randomised, double-blind, placebo-controlled phase 2 trial","volume":"16","author":"Bertini","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.nmd.2005.03.004","article-title":"A motor function measure scale for neuromuscular diseases. Construction and validation study","volume":"15","author":"Payan","year":"2005","journal-title":"Neuromuscul. Disord."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Trundell, D., Le Scouiller, S., Le Goff, L., Gorni, K., and Vuillerot, C. (2020). Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with Type 2 or non-ambulant Type 3 spinal muscular atrophy. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238786"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s40120-020-00206-3","article-title":"Validity and Reliability of the 32-Item Motor Function Measure in 2-to 5-Year-Olds with Neuromuscular Disorders and 2-to 25-Year-Olds with Spinal Muscular Atrophy","volume":"9","author":"Trundell","year":"2020","journal-title":"Neurol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Duong, T., Staunton, H., Braid, J., Barriere, A., Trzaskoma, B., Gao, L., Willgoss, T., Cruz, R., Gusset, N., and Gorni, K. (2022). A Patient-Centered Evaluation of Meaningful Change on the 32-Item Motor Function Measure in Spinal Muscular Atrophy Using Qualitative and Quantitative Data. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.770423"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1016\/j.apmr.2013.01.014","article-title":"Responsiveness of the Motor Function Measure in Patients with Spinal Muscular Atrophy","volume":"94","author":"Vuillerot","year":"2013","journal-title":"Arch. Phys. Med. Rehabilitation"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Seferian, A.M., Moraux, A., Canal, A., Decostre, V., Diebate, O., Le Moing, A.G., Gidaro, T., Deconinck, N., Van Parys, F., and Vereecke, W. (2015). Upper Limb Evaluation and One-Year Follow Up of Non-Ambulant Patients with Spinal Muscular Atrophy: An Observational Multicenter Trial. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121799"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1097\/PHM.0000000000001869","article-title":"Systematic Review of Motor Function Scales and Patient-Reported Outcomes in Spinal Muscular Atrophy","volume":"101","author":"Wu","year":"2021","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1186\/s13023-022-02547-8","article-title":"Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: A prospective 3-years SMArtCARE registry study","volume":"17","author":"Pechmann","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_68","unstructured":"(2023, December 31). National Library of Medicine, Available online: https:\/\/clinicaltrials.gov\/study\/NCT02908685."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/mus.26419","article-title":"Revised upper limb module for spinal muscular atrophy: 12 month changes","volume":"59","author":"Pera","year":"2019","journal-title":"Muscle Nerve"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1136\/jnnp-2020-323822","article-title":"Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3","volume":"91","author":"Maggi","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Ramsey, D., Scoto, M., Mayhew, A., Main, M., Mazzone, E.S., Montes, J., de Sanctis, R., Young, S.D., Salazar, R., and Glanzman, A.M. (2017). Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172346"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Stimpson, G., Ramsey, D., Wolfe, A., Mayhew, A., Scoto, M., Baranello, G., Lofra, R.M., Main, M., Milev, E., and Coratti, G. (2023). 2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants. J. Clin. Med., 12.","DOI":"10.1101\/2023.01.26.23284932"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Ramsey, D., Ramdharry, G., Scoto, M., Muntoni, F., Wallace, A., and on behalf of the SMA REACH UK Network (2022). Revised Hammersmith Scale for spinal muscular atrophy: Inter and intra-rater reliability and agreement. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0278996"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/mus.25430","article-title":"Revised upper limb module for spinal muscular atrophy: Development of a new module","volume":"55","author":"Mazzone","year":"2017","journal-title":"Muscle Nerve"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.nmd.2021.10.009","article-title":"Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes","volume":"32","author":"Coratti","year":"2021","journal-title":"Neuromuscul. Disord."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"120059","DOI":"10.1016\/j.jns.2021.120059","article-title":"Development of the SMA independence scale\u2013upper limb module (SMAIS\u2013ULM): A novel scale for individuals with Type 2 and non-ambulant Type 3 SMA","volume":"432","author":"Trundell","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1097\/BPO.0b013e31820fc522","article-title":"Development and Initial Validation of the Assessment of Caregiver Experience with Neuromuscular Disease","volume":"31","author":"Matsumoto","year":"2011","journal-title":"J. Pediatr. Orthop."},{"key":"ref_78","unstructured":"(2024, June 06). SMAtrial. Available online: https:\/\/www.smatrial.com."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s13023-021-01758-9","article-title":"Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?","volume":"16","author":"Kourakis","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/965631","article-title":"Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy","volume":"2014","author":"Kharraz","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3233\/JND-200556","article-title":"Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy","volume":"8","author":"Quattrocelli","year":"2021","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1474-4422(18)30024-3","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_83","unstructured":"(2024, June 06). U.S. Food and Drug Administration, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.nmd.2019.11.002","article-title":"244th ENMC international workshop: Newborn screening in spinal muscular atrophy May 10\u201312, 2019, Hoofdorp, The Netherlands","volume":"30","author":"Dangouloff","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Nishio, H., Niba, E.T.E., Saito, T., Okamoto, K., Takeshima, Y., and Awano, H. (2023). Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241511939"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1080\/13543784.2021.1904889","article-title":"Therapeutic interventions for spinal muscular atrophy: Preclinical and early clinical development opportunities","volume":"30","author":"Servais","year":"2021","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/mus.23937","article-title":"Rasch analysis of clinical outcome measures in spinal muscular atrophy","volume":"49","author":"Cano","year":"2013","journal-title":"Muscle Nerve"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1007\/s00415-023-11560-1","article-title":"Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA)","volume":"270","author":"Oskoui","year":"2023","journal-title":"J. Neurol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1097\/PEP.0000000000000968","article-title":"Scoring People with Spinal Muscular Atrophy on the Motor Function Measure Using the Microsoft Kinect","volume":"35","author":"Rippert","year":"2023","journal-title":"Pediatr. Phys. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Panero, E., D\u2019alessandro, R., Cavallina, I., Davico, C., Mongini, T., Gastaldi, L., and Ricci, F. (2023). Wearable Inertial Devices in Duchenne Muscular Dystrophy: A Scoping Review. Appl. Sci., 13.","DOI":"10.3390\/app13031268"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41591-022-02045-1","article-title":"Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy","volume":"29","author":"Ricotti","year":"2023","journal-title":"Nat. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1159\/000517411","article-title":"First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases","volume":"5","author":"Servais","year":"2021","journal-title":"Digit. Biomarkers"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1038\/s41591-023-02459-5","article-title":"First regulatory qualification of a digital primary endpoint to measure treatment efficacy in DMD","volume":"29","author":"Servais","year":"2023","journal-title":"Nat. Med."},{"key":"ref_94","unstructured":"(2024, May 30). Ohio State News. Available online: https:\/\/news.osu.edu\/first-wearable-health-sensor-for-monitoring-muscle-atrophy\/."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Iijima, K., Watanabe, H., Nakashiro, Y., Iida, Y., Nonaka, M., Moriwaka, F., and Hamada, S. (2023). Long-term effects of the gait treatment using a wearable cyborg hybrid assistive limb in a patient with spinal and bulbar muscular atrophy: A case report with 5 years of follow-up. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1143820"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/dmcn.15286","article-title":"Financial cost and quality of life of patients with spinal muscular atrophy identified by symptoms or newborn screening","volume":"65","author":"Dangouloff","year":"2022","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1001\/jamapediatrics.2024.0489","article-title":"Universal Newborn Screening for Spinal Muscular Atrophy","volume":"178","author":"Oskoui","year":"2024","journal-title":"JAMA Pediatr."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1001\/jamapediatrics.2024.0492","article-title":"Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy","volume":"178","author":"Schwartz","year":"2024","journal-title":"JAMA Pediatr."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1002\/cpt.2247","article-title":"Prognostic Factors and Treatment-Effect Modifiers in Spinal Muscular Atrophy","volume":"110","author":"Baranello","year":"2021","journal-title":"Clin. Pharmacol. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10273\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:01:45Z","timestamp":1760112105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,24]]},"references-count":99,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910273"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910273","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,24]]}}}