Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis
Bernardo-Faura, Martí (Centre de Recerca en Agrigenòmica)
Rinas, Melanie (Rwth Aachen University. Joint Research Center for Computational Biomedicine)
Wirbel, Jakob (Rwth Aachen University. Joint Research Center for Computational Biomedicine)
Pertsovskaya, Inna (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Pliaka, Vicky (School of Mechanical Engineering, National Technical University of Athens)
Messinis, Dimitris E. (ProtATonce)
Vila, Gemma (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Sakellaropoulos, Theodore (National Technical University of Athens)
Faigle, Wolfgang (University of Zurich)
Stridh, Pernilla (Karolinska Institutet (Estocolm, Suècia). Department of Clinical Neuroscience)
Behrens, Janina R. (Charité University Medicine Berlin. NeuroCure Clinical Research Center and Department of Neurology)
Olsson, Tomas (Karolinska Institutet (Estocolm, Suècia). Department of Clinical Neuroscience)
Martin, Roland (University Hospital Zurich (Suïssa))
Paul, Friedemann (Charité University Medicine Berlin. NeuroCure Clinical Research Center and Department of Neurology)
Alexopoulos, Leonidas G. (ProtATonce)
Villoslada, Pablo (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Saez-Rodriguez, Julio (Heidelberg University Hospital (Alemanya))

Date:	2021
Abstract:	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. 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-β, 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 "healthy-like" status by combination therapy. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS was used to validate the prediction of combination therapies. 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-β activated kinase 1 (TAK1) kinase, involved in Transforming growth factor β-1 proprotein (TGF-β), 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. Our approach based on donor-specific signaling networks enables prediction of targets for combination therapy for MS and other complex diseases.
Grants:	European Commission 305397 European Commission 340733
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Signaling networks ; Pathways ; Network modeling ; Logic modeling ; Kinases ; Treatment ; Personalized medicine ; Combination therapy ; Multiple sclerosis ; Immunotherapy ; Phosphoproteomics ; Xmap assay
Published in:	Genome Medicine, Vol. 13 (July 2021) , art. 117, ISSN 1756-994X

DOI: 10.1186/s13073-021-00925-8
PMID: 34271980

16 p, 3.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > CRAG (Centre for Research in Agricultural Genomics)
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