Developing therapeutic strategies to promote myelin repair in multiple sclerosis

ABSTRACT

Introduction: Approved disease-modifying therapies for multiple sclerosis (MS) lessen inflammatory disease activity that causes relapses and MRI lesions. However, chronic inflammation and demyelination lead to axonal degeneration and neuronal loss, for which there currently is no effective treatment. There has been increasing interest in developing repair-promoting strategies, but there are important unanswered questions regarding the mechanisms and appropriate methods to evaluate these treatments.

Areas covered: The rationale for remyelinating agents in MS is discussed, with an overview of both myelin physiology and endogenous repair mechanisms. This is followed by a discussion of the identification and development of potential remyelinating drugs. Potential biomarkers of remyelination are reviewed, including considerations regarding measuring remyelination in clinical trials. Information and data were obtained from a search of recent literature through PubMed. Peer-reviewed original articles and review articles were included.

Expert opinion: There are several obstacles to the translation of potential remyelinating agents to clinical trials, particularly uncertainty regarding the most appropriate study population and method to monitor remyelination. Refinements in clinical trial design and outcome measurement, potentially via advanced imaging techniques, are needed to optimize detection of repair in patients with MS.

KEYWORDS:

• Advanced imaging
• biomarkers
• multiple sclerosis
• remyelination
• repair
• mesenchymal stem cells

Article highlights

• Multiple sclerosis is a frequently disabling immune-mediated neurodegenerative disease of the central nervous system characterized by chronic demyelination, ultimately leading to axonal degeneration, particularly in progressive stages of the disease.

• Current disease-modifying therapies for multiple sclerosis lessen inflammatory disease activity that leads to relapses and MRI lesion activity, but remyelination strategies could potentially fill a major unmet need by addressing the neurodegenerative aspects of the disease process.

• Novel high-throughput screening techniques have identified potential remyelinating agents, including clemastine fumarate, benztropine, and miconazole, that potentially can augment the function of endogenous oligodendrocyte progenitor cells.

• Other potential remyelinating agents under investigation in clinical trials include mesenchymal stem cells, high-dose biotin, and opicinumab.

• Availability of both sensitive and specific imaging or fluid biomarkers to quantify myelin loss and replacement with clinical relevance would be of significant benefit to clinical trial design.

• Optimization of clinical trial design to test remyelinating strategies is needed.

• Although significant progress in the development of remyelination has been made, further work to identify new candidate strategies and refine the methodology to test them is needed to translate such advances to clinical care.

Acknowledgments

The authors wish to acknowledge the Cleveland Clinic Center for Medical Art & Photography for their assistance in producing Figure 1.

Declaration of interest

LE Baldassari has received personal consulting fees for serving on an advisory board for Teva. She also receives funding via a Sylvia Lawry Physician Fellowship Grant through the National Multiple Sclerosis Society(#FP-1606-24540). J Feng has served on a scientific board for Sanofi. She also receives funding via a Sylvia Lawry Physician Fellowship Grant through the National Multiple Sclerosis Society(#FP-1707-28768). JA Cohen has received personal fees for cosulting for Alkermes, Biogen, Convelo, EMD Sereno, ERT, Gossamer Bio, Novartis, and ProValuate. He has also received personal fees for speaking for Mylan and Synthon as well as serving as an Editor of Multiple Sclerosis Journal. SH Oh receives salary support from the Hankuk University of Foreign Studies research fund. K Sakaie receives salary support from Novartis and Genzyme. P Tesar is a co-founder and holds equity in Convelo Therapeutics and has received personal consulting fees from Convelo Therapeutics, Cell Line Genetics, BlueRock Therapeutics, and Third Rock Ventures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded