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Remyelination therapies: a new direction and challenge in multiple sclerosis

Key Points

  • People with multiple sclerosis exhibit variable degrees of remyelination.

  • Individuals with greater capacity to remyelinate seem to have less clinical disability, thereby fuelling the research to find remyelination therapeutics for multiple sclerosis.

  • The biology of remyelination and its similarities and differences from developmental myelination are discussed.

  • Many pro-remyelinating therapeutics have been identified from experimental models.

  • Early phase clinical trials with potential pro-remyelinating therapeutics are in progress.

  • Many challenges remain on how best to perform clinical trials of potential pro-remyelinating medications for multiple sclerosis.

Abstract

Multiple sclerosis is characterized by inflammatory activity that results in destruction of the myelin sheaths that enwrap axons. The currently available medications for multiple sclerosis are predominantly immune-modulating and do not directly promote repair. White matter regeneration, or remyelination, is a new and exciting potential approach to treating multiple sclerosis, as remyelination repairs the damaged regions of the central nervous system. A wealth of new strategies in animal models that promote remyelination, including the repopulation of oligodendrocytes that produce myelin, has led to several clinical trials to test new reparative therapies. In this Review, we highlight the biology of, and obstacles to, remyelination. We address new strategies to improve remyelination in preclinical models, highlight the therapies that are currently undergoing clinical trials and discuss the challenges of objectively measuring remyelination in trials of repair in multiple sclerosis.

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Figure 1: Regulation of remyelination.
Figure 2: Drugs that affect myelin reformation and are prospective medications for repair in multiple sclerosis.
Figure 3: Proposed method for efficiently finding remyelinating therapies in multiple sclerosis.

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Acknowledgements

The authors' research on remyelination has been funded by operating grants from the Alberta Innovates Health Solutions CRIO Team Program, the Multiple Sclerosis Society of Canada and the Canadian Institutes of Health Research. The authors thank A. Caprariello, S. Jensen, M. Keough, G. Duncan and K. Rawji for critically reading this manuscript.

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Correspondence to V. Wee Yong.

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Glossary

Relapsing–remitting MS

A form of multiple sclerosis (MS) that is characterized by episodes or attacks, called relapses, which cause neurologic dysfunction with variable recovery over time, interspersed with periods of stability (also known as remission).

Progressive MS

A form of multiple sclerosis (MS) that is characterized by a slow accumulation of disability without relapses. It is classified as primary progressive MS if patients present with a progressive disease course from onset and secondary progressive MS if patients initially present with a course of relapsing–remitting MS and later convert to progressive disease.

Oligodendrocyte

A type of neuroglial cell that produces myelin.

Compact myelin

In the central nervous system, the wrapping of multiple layers of oligodendrocyte membrane forms myelin. In its mature form, these membrane layers become compact.

Nodes of Ranvier

Gaps between two adjacent myelinated regions where the axon is exposed to the extracellular space.

Oligodendrocyte progenitor cells

Cells that express the characteristic markers platelet-derived growth factor receptor-α (PDGFRα) and chondroitin sulfate proteoglycan 4 (CSPG4, also known as NG2), and that mature into oligodendrocytes during development and remyelination. These cells are also referred to as polydendrocytes or NG2 cells.

White matter

Areas of the central nervous system containing primarily myelinated axons. Owing to the lipid-rich composition of myelin, these areas appear white compared with adjacent areas.

Grey matter

Areas of the central nervous system containing less myelination; it is enriched with neuronal cell bodies and dendrites.

Visual evoked potential

The measured surface electrical activity in the brain in response to visual stimulation.

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Plemel, J., Liu, WQ. & Yong, V. Remyelination therapies: a new direction and challenge in multiple sclerosis. Nat Rev Drug Discov 16, 617–634 (2017). https://doi.org/10.1038/nrd.2017.115

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