{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T11:06:59Z","timestamp":1788001619799,"version":"build-2784847793"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T00:00:00Z","timestamp":1626393600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T00:00:00Z","timestamp":1626393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"European Union 7FP-Programme","award":["CombiMS, grant No 305397"],"award-info":[{"award-number":["CombiMS, grant No 305397"]}]},{"name":"European Sys4MS project","award":["Horizon2020: Eracosysmed: ID-43"],"award-info":[{"award-number":["Horizon2020: Eracosysmed: ID-43"]}]},{"name":"European Research Council Advanced Gran","award":["ERC 340733-HLA-DR15 in MS"],"award-info":[{"award-number":["ERC 340733-HLA-DR15 in MS"]}]},{"name":"Swiss National Science Foundation and the Swiss MS Society","award":["Clinical Research Priority Project - disease heterogeneity of MS (CRPPMS; UZH)"],"award-info":[{"award-number":["Clinical Research Priority Project - disease heterogeneity of MS (CRPPMS; UZH)"]}]},{"DOI":"10.13039\/501100001661","name":"Ruprecht-Karls-Universit\u00e4t Heidelberg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001661","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) is a major health problem, leading to a significant disability and patient suffering. Although chronic activation of the immune system is a hallmark of the disease, its pathogenesis is poorly understood, while current treatments only ameliorate the disease and may produce severe side effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we applied a network-based modeling approach based on phosphoproteomic data to uncover the differential activation in signaling wiring between healthy donors, untreated patients, and those under different treatments. Based in the patient-specific networks, we aimed to create a new approach to identify drug combinations that revert signaling to a healthy-like state. We performed ex vivo multiplexed phosphoproteomic assays upon perturbations with multiple drugs and ligands in primary immune cells from 169 subjects (MS patients, n=129 and matched healthy controls, n=40). Patients were either untreated or treated with fingolimod, natalizumab, interferon-\u03b2, glatiramer acetate, or the experimental therapy epigallocatechin gallate (EGCG). We generated for each donor a dynamic logic model by fitting a bespoke literature-derived network of MS-related pathways to the perturbation data. Last, we developed an approach based on network topology to identify deregulated interactions whose activity could be reverted to a \u201chealthy-like\u201d status by combination therapy. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS was used to validate the prediction of combination therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Analysis of the models uncovered features of healthy-, disease-, and drug-specific signaling networks. We predicted several combinations with approved MS drugs that could revert signaling to a healthy-like state. Specifically, TGF-\u03b2 activated kinase 1 (TAK1) kinase, involved in Transforming growth factor \u03b2-1 proprotein (TGF-\u03b2), Toll-like receptor, B cell receptor, and response to inflammation pathways, was found to be highly deregulated and co-druggable with all MS drugs studied. One of these predicted combinations, fingolimod with a TAK1 inhibitor, was validated in an animal model of MS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our approach based on donor-specific signaling networks enables prediction of targets for combination therapy for MS and other complex diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-021-00925-8","type":"journal-article","created":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T06:02:57Z","timestamp":1626415377000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis"],"prefix":"10.1186","volume":"13","author":[{"given":"Marti","family":"Bernardo-Faura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Rinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Wirbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Pertsovskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"Pliaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris E.","family":"Messinis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Vila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore","family":"Sakellaropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Faigle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernilla","family":"Stridh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina R.","family":"Behrens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedemann","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas G.","family":"Alexopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Villoslada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8552-8976","authenticated-orcid":false,"given":"Julio","family":"Saez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,16]]},"reference":[{"issue":"3","key":"925_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/nrd2275","volume":"6","author":"J Owens","year":"2007","unstructured":"Owens J. 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All appropriate IRB approvals to use the data from the clinical studies and the EGCG trial were obtained from these IRB committees with the following committee reference numbers. University of Zurich: Approved by the Cantonal Ethics Board of the Canton of Zurich, EC-Nr. 2013-0001. Karolinska Institutet: Approved by Regionala etikpr\u00f6vningsn\u00e4mnden i Stockholm: Stop MS II, EC-Nr. 2009\/2107-31\/2. IDIBAPS: Approved by Comite de Etica Medica Hospital Clinic Barcelona, EC-Nr: 2012-7662. Charit\u00e9 University Medicine Berlin: Approved by Ethikkommission des Landes Berlin am Landesamt f\u00fcr Gesundheit und Soziales, EC-Nr. 2006-006323-39. Readers can gain access to the EGCG trial data as described in the original publication [\n                      \n                      ] by contacting\n                      \n                      , as far as permitted according to data protection requirements and consent provided by the participants. The research conformed to the principles of the Helsinki Declaration.All animal handling was carried out in accordance with the European Council Directive (2010\/63\/EU) and the Spanish regulations for the procurement and care of experimental animals (1201 RD\/2005, October 10). All the study protocols were approved by the Ethical Committee on Animal Research of the University of Barcelona.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"DEM is an employee of ProtATonce; TO has received honoraria for lectures and\/or advisory boards as well as unrestricted multiple sclerosis research grants from Allmiral, Astrazeneca, Biogen, Genzyme, Merck, and Novartis; RM reports grants and personal compensation from Biogen, personal fees from Genzyme Sanofi Aventis, grants and personal fees from Novartis, and personal fees from Merck Serono, Roche, Neuway, and CellProtect, outside the submitted work; FP has received research grants and personal compensation for activities with Alexion, Bayer, Chugai, Novartis, Merck, Teva, Sanofi, Genzyme, Biogen, and MedImmune; LGA is the founder and hold stocks at ProtATonce; PV holds stocks and has received consultancy fees from Bionure Farma SL, Spiral Therapeutics Inc., Spire Bioventures Inc., Attune Neurosciences Inc., QMenta Inc., and Health Engineering SL; JSR declares funding from GSK and Sanofi and consultant fees from Travere Therapeutics. The other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"117"}}