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Emerging therapies to target CNS pathophysiology in multiple sclerosis

Abstract

The rapidly evolving therapeutic landscape of multiple sclerosis (MS) has contributed to paradigm shifts in our understanding of the biological mechanisms that contribute to CNS injury and in treatment philosophies. Opportunities remain to further improve treatment of relapsing–remitting MS, but two major therapeutic gaps are the limiting of progressive disease mechanisms and the repair of CNS injury. In this Review, we provide an overview of selected emerging therapies that predominantly target processes within the CNS that are thought to be involved in limiting non-relapsing, progressive disease injury or promoting tissue repair. Among these, we consider agents that modulate adaptive and innate CNS-compartmentalized inflammation, which can be mediated by infiltrating immune cells and/or resident CNS cells, including microglia and astrocytes. We also discuss agents that target degenerative disease mechanisms, agents that might confer neuroprotection, and agents that create a more favourable environment for or actively contribute to oligodendrocyte precursor cell differentiation, remyelination and axonal regeneration. We focus on agents that are novel for MS, that are known to or are presumed to penetrate the CNS, and that have already entered early stages of development in MS clinical trials.

Key points

  • Therapeutic agents that limit progressive disease mechanisms and repair CNS injury are an important unmet need in multiple sclerosis (MS) clinical practice.

  • A number of emerging therapies target compartmentalized inflammation, remyelination and neuroprotection, and could be beneficial in progressive MS and CNS repair.

  • Emerging therapies that target CNS inflammation include Bruton tyrosine kinase inhibitors, CD40 ligand antibodies and α-lipoic acid.

  • Emerging therapies that provide neuroprotection include masitinib, ibudilast, metformin, clomipramine and receptor-interacting protein kinase 1.

  • Emerging therapies that disinhibit CNS repair include elezanumab and opicinumab, and those that promote CNS repair include proteoglycans, niacin, muscarinic receptor antagonists and temelimab.

  • Many candidate drugs require validation in large clinical trials, but their emergence opens the door to new treatment algorithms and personalized therapy in MS.

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The authors contributed equally to all aspects of the article.

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Correspondence to Amit Bar-Or.

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J.O. holds the Waugh Family Chair in MS Research and has received research funding from the Barford/Love MS Fund of St. Michael’s Hospital, Biogen-Idec, Brain Canada, EMD-Serono, the MS Society of Canada, the National MS Society, the National Institutes of Health, and Roche. She has received compensation for consulting or speaking from Biogen-Idec, BMS, EMD-Serono, Novartis, Roche and Sanofi-Genzyme. A.B.-O. holds the Melissa and Paul Anderson Chair. He has received research funding from the Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation, Multiple Sclerosis Society of Canada, the Multiple Sclerosis Scientific Foundation, the National Institutes of Health and the National MS Society. He has participated as a speaker in meetings sponsored by and received consulting fees from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi-Genzyme. He has received grant support to the University of Pennsylvania from Biogen Idec, Merck/EMD Serono, Novartis and Roche/Genentech.

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Nature Reviews Neurology thanks A. Bertolotto; D. Centonze, who co-reviewed with A. Gentile; and B. Weinstock-Guttman for their contribution to the peer review of this work.

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Oh, J., Bar-Or, A. Emerging therapies to target CNS pathophysiology in multiple sclerosis. Nat Rev Neurol (2022). https://doi.org/10.1038/s41582-022-00675-0

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