{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T01:55:26Z","timestamp":1777600526973,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T00:00:00Z","timestamp":1615593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ME 3696\/3-1"],"award-info":[{"award-number":["ME 3696\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.<\/jats:p>","DOI":"10.3390\/brainsci11030367","type":"journal-article","created":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T22:13:10Z","timestamp":1615759990000},"page":"367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients"],"prefix":"10.3390","volume":"11","author":[{"given":"Alma","family":"Osmanovic","sequence":"first","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-4487","authenticated-orcid":false,"given":"Olivia","family":"Schreiber-Katz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Petri","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s40265-017-0711-7","article-title":"Nusinersen: First Global Approval","volume":"77","author":"Hoy","year":"2017","journal-title":"Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1212\/WNL.0000000000002445","article-title":"Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy","volume":"86","author":"Chiriboga","year":"2016","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1146\/annurev-pharmtox-010919-023738","article-title":"Antisense Drugs Make Sense for Neurological Diseases","volume":"61","author":"Bennett","year":"2021","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/jcph.884","article-title":"Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations","volume":"57","author":"Luu","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"ref_5","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_6","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_7","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_8","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1474-4422(20)30037-5","article-title":"Nusinersen in adults with 5q spinal muscular atrophy: A non-interventional, multicentre, observational cohort study","volume":"19","author":"Hagenacker","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_9","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_10","first-page":"e413","article-title":"Nusinersen in adult patients with spinal muscular atrophy: Observations from a single center","volume":"95","author":"Visser","year":"2020","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.pcl.2015.03.010","article-title":"Spinal muscular atrophies","volume":"62","author":"Darras","year":"2015","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"523","DOI":"10.3233\/JND-200534","article-title":"Measuring Outcomes in Adults with Spinal Muscular Atrophy-Challenges and Future Directions-Meeting Report","volume":"7","author":"Sansone","year":"2020","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Binz, C., Schreiber-Katz, O., Kumpe, M., Ranxha, G., Siegler, H., Wieselmann, G., Petri, S., and Osmanovic, A. (2020). An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment. J. Neurol.","DOI":"10.1007\/s00415-020-10227-5"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1756286421998902","DOI":"10.1177\/1756286421998902","article-title":"Treatment satisfaction in 5q-spinal muscular atrophy under nusinersen therapy","volume":"14","author":"Osmanovic","year":"2021","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3233\/JND-190453","article-title":"Prospective Cohort Study of Nusinersen Treatment in Adults with Spinal Muscular Atrophy","volume":"7","author":"Yeo","year":"2020","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1517\/14656566.7.10.1399","article-title":"The levodopa wearing-off phenomenon in Parkinson\u2019s disease: Pharmacokinetic considerations","volume":"7","author":"Stocchi","year":"2006","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Montes, J., McDermott, M.P., Mirek, E., Mazzone, E.S., Main, M., Glanzman, A.M., Duong, T., Young, S.D., Salazar, R., and Pasternak, A. (2018). Ambulatory function in spinal muscular atrophy: Age-related patterns of progression. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199657"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pera, M.C., Coratti, G., Forcina, N., Mazzone, E.S., Scoto, M., Montes, J., Pasternak, A., Mayhew, A., Messina, S., and Sframeli, M. (2017). Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol., 17.","DOI":"10.1186\/s12883-017-0790-9"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1212\/WNL.0b013e318271f7e4","article-title":"Prospective cohort study of spinal muscular atrophy types 2 and 3","volume":"79","author":"Kaufmann","year":"2012","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Osmanovic, A., Ranxha, G., Kumpe, M., Muschen, L., Binz, C., Wiehler, F., Paracka, L., Korner, S., Kollewe, K., and Petri, S. (2020). Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy. J. Neurol.","DOI":"10.1007\/s00415-020-09847-8"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1743-8454-5-10","article-title":"Multiplicity of cerebrospinal fluid functions: New challenges in health and disease","volume":"5","author":"Johanson","year":"2008","journal-title":"Cereb. Fluid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/cercor\/11.4.335","article-title":"Age-related volumetric changes of brain gray and white matter in healthy infants and children","volume":"11","author":"Matsuzawa","year":"2001","journal-title":"Cereb. Cortex"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4817","DOI":"10.1172\/JCI124120","article-title":"Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment","volume":"129","author":"Ramos","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1097\/00000542-199606000-00010","article-title":"Magnetic resonance imaging of cerebrospinal fluid volume and the influence of body habitus and abdominal pressure","volume":"84","author":"Hogan","year":"1996","journal-title":"Anesthesiology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e149","DOI":"10.1212\/WNL.0000000000007742","article-title":"Natural course of scoliosis and lifetime risk of scoliosis surgery in spinal muscular atrophy","volume":"93","author":"Wijngaarde","year":"2019","journal-title":"Neurology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/mus.26903","article-title":"Spinal muscular atrophy care in the COVID-19 pandemic era","volume":"62","author":"Veerapandiyan","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2003715","article-title":"Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS","volume":"383","author":"Miller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e00447","DOI":"10.1002\/prp2.447","article-title":"Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs","volume":"6","author":"Poirier","year":"2018","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2633105520973985","DOI":"10.1177\/2633105520973985","article-title":"The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy","volume":"15","author":"Singh","year":"2020","journal-title":"Neurosci. 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