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It's Time For Combination Therapies: in Multiple Sclerosis.

ABSTRACT: The treatment of multiple sclerosis continues to evolve. However, even with the introduction of B-cell depleting monoclonal antibodies, disability progression continues unabated since B-cell therapies are unable to cross the blood brain barrier and thus are unable to address the disease that lurks within the brain. In this commentary, the author explores the research and practice of using B-cell depleting monoclonal antibody therapies in MS. The author provides discussion on the blood brain barrier as the primary limitation to the effectiveness of MS therapies. The author briefly reviews the pathophysiological role of B-cells in MS and the implications that B-cell migration to the brain has on MS disease progression and treatment. The author discusses potential drug development strategies for MS that combine blood brain barrier crossing molecules with peripherally acting B-cell depleting monoclonal antibodies.

SUBMITTER: Avasarala J

PROVIDER: S-EPMC5605202 | biostudies-literature | 2017 May-Jun

REPOSITORIES: biostudies-literature

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It's Time For Combination Therapies: in Multiple Sclerosis.

Avasarala Jagannadha J

Innovations in clinical neuroscience 20170501 5-6

The treatment of multiple sclerosis continues to evolve. However, even with the introduction of B-cell depleting monoclonal antibodies, disability progression continues unabated since B-cell therapies are unable to cross the blood brain barrier and thus are unable to address the disease that lurks within the brain. In this commentary, the author explores the research and practice of using B-cell depleting monoclonal antibody therapies in MS. The author provides discussion on the blood brain barr ...[more]

PMID: 28979825

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Project description:BackgroundMultiple 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.MethodsHere, 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.ResultsAnalysis 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.ConclusionsOur approach based on donor-specific signaling networks enables prediction of targets for combination therapy for MS and other complex diseases.

Dataset Information

It's Time For Combination Therapies: in Multiple Sclerosis.

Publications

It's Time For Combination Therapies: in Multiple Sclerosis.

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