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Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis

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Item Type:Article
Title:Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis
Creators Name:Bernardo-Faura, M. and Rinas, M. and Wirbel, J. and Pertsovskaya, I. and Pliaka, V. and Messinis, D.E. and Vila, G. and Sakellaropoulos, T. and Faigle, W. and Stridh, P. and Behrens, J.R. and Olsson, T. and Martin, R. and Paul, F. and Alexopoulos, L.G. and Villoslada, P. and Saez-Rodriguez, J.
Abstract:BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS. Our approach based on donor-specific signaling networks enables prediction of targets for combination therapy for MS and other complex diseases.
Keywords:Signaling Networks, Pathways, Network Modeling, Logic Modeling, Kinases, Treatment, Personalized Medicine, Combination Therapy, Multiple Sclerosis, Immunotherapy, Phosphoproteomics, xMAP Assay
Source:Genome Medicine
Publisher:BioMed Central
Page Range:117
Date:16 July 2021
Official Publication:https://doi.org/10.1186/s13073-021-00925-8
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/18194/Preprint version

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