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  • Review Article
  • Published:

Achievements and obstacles of remyelinating therapies in multiple sclerosis

Nature Reviews Neurology volume 13, pages 742–754 (2017)Cite this article

Subjects

Key Points

  • CNS remyelination serves to limit and repair the damage in demyelinating diseases such as multiple sclerosis (MS)

  • Several intrinsic molecular pathways that execute endogenous remyelination have been identified and are potential therapeutic targets

  • The first clinical proof-of-concept trials to enhance remyelination in MS have been conducted in the past few years

  • The optimal clinical and paraclinical outcome measures for the assessment of remyelination are not known, but neurophysiological measures, MRI, myelin-targeted PET radiotracers, and optical coherence tomography all are possible adjuncts to clinical outcomes in proof-of-concept studies

  • The timing of remyelination therapy is a crucial issue

  • Future MS therapy is likely to involve a combination of immunomodulatory and regenerative treatments

Abstract

Remyelination in the CNS is the natural process of damage repair in demyelinating diseases such as multiple sclerosis (MS). However, remyelination becomes inadequate in many people with MS, which results in axonal degeneration and clinical disability. Enhancement of remyelination is a logical therapeutic goal; nevertheless, all currently licensed therapies for MS are immunomodulatory and do not support remyelination directly. Several molecular pathways have been identified as potential therapeutic targets to induce remyelination, and some of these have now been assessed in proof-of-concept clinical trials. However, trial design faces several obstacles: optimal clinical or paraclinical outcome measures to assess remyelination remain ill-defined, and identification of the ideal timing of therapy is also a crucial issue. In addition, realistic expectations are needed concerning the probable benefits of such therapies. Nevertheless, approaches that enhance remyelination are likely to be protective for axons and so could prevent long-term neurodegeneration. Future MS treatment paradigms, therefore, are likely to comprise a combinatorial approach that involves both immunomodulatory and regenerative treatments.

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Figure 1: Cellular factors involved in remyelination.
Figure 2: Summary of molecular factors controlling remyelination.
Figure 3: Histological features of remyelination in multiple sclerosis.
Figure 4: Dynamic myelin changes in relapsing–remitting multiple sclerosis, detected by MRI.

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Acknowledgements

This study was supported by grants to T.K. from the German Research Foundation (SFB-TR128-B7; Ku1477/6-1) and the Interdisciplinary Clinical Research Center, Münster (IZKF; KuT3/012/15). P.M.M. is in receipt of personal and research support from the Edmond J. Safra Foundation and Lily Safra, the Imperial College National Institute for Health Research (NIHR) Biomedical Research Centre, the NIHR Senior Investigator Programme, the UK Dementia Research Institute, the UK Medical Research Council, Biogen and the Engineering and Physics Science Research Council. M.S. is supported by Niedersachsen Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony.

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Authors and Affiliations

  1. Department of Neurology, Clinical Neuroimmunology and Neurochemistry, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, 30625, Germany

    Martin Stangel

  2. Institute of Neuropathology, University Hospital Münster, Pottkamp 2, Münster, 48149, Germany

    Tanja Kuhlmann

  3. Division of Brain Sciences, Department of Medicine, and UK Dementia Research Institute, Imperial College London, Burlington Danes, Hammersmith Hospital, DuCane Road, London, W12 0NN, UK

    Paul M. Matthews

  4. Department of Anatomy and Neuroscience and Melbourne Neuroscience Institute, University of Melbourne, 30 Royal Parade, Parkville, 3010, Victoria, Australia

    Trevor J. Kilpatrick

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  1. Martin Stangel
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  2. Tanja Kuhlmann
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  4. Trevor J. Kilpatrick
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All authors performed literature searches, selected important literature to be cited, wrote various sections of the manuscript, and revised the entire manuscript.

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Correspondence to Martin Stangel.

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Glossary

G-ratio

The ratio of the inner axonal diameter to the total outer diameter, an index of relative myelin thickness

Uhthoff's phenomenon

Heat-associated worsening of neurological symptoms caused by inhibition of nerve conduction following demyelination.

Shadow plaques

Multiple sclerosis lesions in which the total lesion area is remyelinated.

Heterochronic parabiosis

Surgical joining of two animals of different ages to generate a shared circulation.

Optical coherence tomography

An optical imaging method that provides detailed information regarding the microstructure of thin layers of tissue (for example, the retina) based on backscatter of reflected light.

Diffusion-weighted MRI

An MRI method in which the contrast-reflecting tissue microstructure is determined based on intrinsic local differences in the rate or extent of diffusion of water.

b-value

A scanner parameter conveying the relative strength and timing of the diffusion-sensitising gradients for diffusion-weighted MRI; stronger diffusion effects are imaged with higher b-values.

Q-ball imaging

A form of diffusion MRI developed by Dr David Tuch of Harvard University, USA, which enables multiple white matter fibre orientations to beresolved even within a single voxel.

Magnetization transfer imaging

An imaging method based on the intrinsic contrast provided by differences in the extent of transfer of magnetisation from a macromolecular bound water pool (for example, myelin water) to the bulk water when radiofrequency energy is applied to the bound water pool.

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Stangel, M., Kuhlmann, T., Matthews, P. et al. Achievements and obstacles of remyelinating therapies in multiple sclerosis. Nat Rev Neurol 13, 742–754 (2017). https://doi.org/10.1038/nrneurol.2017.139

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