{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:13:41Z","timestamp":1777029221302,"version":"3.51.4"},"reference-count":31,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0\u201320\u2009years with and without treatment with the antisense oligonucleotide nusinersen. Physiological changes typical of the pediatric age and the contribution of SMA and its treatment to the peripheral pNfH levels were included in the model by extending the equations of a previously developed mathematical model describing the neurofilament trafficking in healthy adults. All model parameters were estimated by fitting data from clinical trials that enrolled SMA patients treated with nusinersen. The data from the control group of the study was employed to build an in silico population of untreated subjects, and the parameters related to the treatment were estimated by fitting individual pNfH time series of SMA patients followed during the treatment. The final model reproduces well the pNfH levels in the presence of SMA in both the treated and untreated conditions. The results were validated by comparing model predictions with the data obtained from an additional cohort of SMA patients. The reported good predictive model performance makes it a valuable tool for investigating pNfH as a biomarker of disease progression and treatment response in SMA and for the in silico evaluation of novel treatment protocols.<\/jats:p>","DOI":"10.1002\/psp4.12890","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T04:30:57Z","timestamp":1670301057000},"page":"196-206","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen"],"prefix":"10.1002","volume":"12","author":[{"given":"Alessio","family":"Paris","sequence":"first","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Centre for Computational and Systems Biology (COSBI) Rovereto Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pranami","family":"Bora","sequence":"additional","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Centre for Computational and Systems Biology (COSBI) Rovereto Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Parolo","sequence":"additional","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Centre for Computational and Systems Biology (COSBI) Rovereto Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Drew","family":"MacCannell","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Monine","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nick","family":"van der Munnik","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0405-6429","authenticated-orcid":false,"given":"Xiao","family":"Tong","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satish","family":"Eraly","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zdenek","family":"Berger","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Graham","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toby","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Domenici","sequence":"additional","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Centre for Computational and Systems Biology (COSBI) Rovereto Italy"},{"name":"Department of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Nestorov","sequence":"additional","affiliation":[{"name":"Biogen, Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9043-7705","authenticated-orcid":false,"given":"Luca","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Centre for Computational and Systems Biology (COSBI) Rovereto Italy"},{"name":"Department of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60921-6"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-71"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0797-265"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702752"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075091"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0058-z"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a018309"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.779"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09547-y"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12770"},{"issue":"15","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1212\/WNL.94.15_supplement.1640","article-title":"Nusinersen in infantile\u2010onset spinal muscular atrophy: results from longer\u2010term treatment from the open\u2010label SHINE extension study (1640)","volume":"94","author":"Castro D","year":"2020","journal-title":"Neurology"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.09.007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27187"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2017.04.1219"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710504"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-006-9018-0"},{"key":"e_1_2_9_18_1","unstructured":"CDC Clinical Grow Charts.2017. Accessed November 22 2022.https:\/\/www.cdc.gov\/growthcharts\/clinical_charts.htm."},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12323"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19971020)387:2<167::AID-CNE1>3.0.CO;2-Z"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1105108108"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/js970414z"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2019-0015"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12063"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0134-5"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2016.06.007"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4547(20000801)61:3<338::AID-JNR12>3.0.CO;2-5"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1819.1999.00610.x"},{"issue":"3","key":"e_1_2_9_29_1","first-page":"46","article-title":"Barrier mechanisms in the developing brain","volume":"29","author":"Saunders NR","year":"2012","journal-title":"Front Pharmacol"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00277658"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-021-09761-0"},{"key":"e_1_2_9_32_1","doi-asserted-by":"crossref","unstructured":"DayJW Pascual\u2010PascualSI FinkelRSet al.Escalating Dose and Randomized Controlled Study of Nusinersen in Participants With Spinal Muscular Atrophy (SMA); Study Design and Part A Data for the Phase 2\/3 DEVOTE (232SM203) Study to Explore High Dose Nusinersen (2343).2021.","DOI":"10.1212\/WNL.96.15_supplement.2343"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12890","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.12890","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12890","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T23:36:13Z","timestamp":1728516973000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.12890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,5]]},"references-count":31,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/psp4.12890"],"URL":"https:\/\/doi.org\/10.1002\/psp4.12890","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,5]]},"assertion":[{"value":"2022-07-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}