{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:29:48Z","timestamp":1780446588132,"version":"3.54.1"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001625","name":"Foundation to Eradicate Duchenne","doi-asserted-by":"publisher","award":["2018"],"award-info":[{"award-number":["2018"]}],"id":[{"id":"10.13039\/100001625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NF\u0138B activation, mitochondrial dysfunction, and induction of TGF\u03b2 fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the <jats:italic>mdx<\/jats:italic> mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old <jats:italic>mdx<\/jats:italic> mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, \u03b2-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6\/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NF\u03baB and TGF\u03b2 cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our <jats:italic>mdx<\/jats:italic> data showed 14% (3\/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.<\/jats:p>","DOI":"10.1371\/journal.pone.0246507","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T18:34:38Z","timestamp":1614018878000},"page":"e0246507","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Biomarker-focused multi-drug combination therapy and repurposing trial in mdx 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