Remyelination therapies for multiple sclerosis: optimizing translation from animal models into clinical trials

ABSTRACT

Introduction: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system (CNS). Demyelination, the main pathology in MS, contributes to clinical symptoms and long-term neurological deficits if left untreated. Remyelination, the natural repair of damaged myelin by cells of the oligodendrocyte lineage, occurs in MS, but eventually fails in most patients as they age. Encouraging timely remyelination can restore axon conduction and minimize deficits.

Areas covered: We discuss and correlate human MS pathology with animal models, propose methods to deplete resident oligodendrocyte progenitor cells (OPCs) to determine whether mature oligodendrocytes support remyelination, and review remyelinating agents, mechanisms of action, and available clinical trial data.

Expert opinion: The heterogeneity of human MS may limit successful translation of many candidate remyelinating agents; some patients lack the biological targets necessary to leverage current approaches. Development of therapeutics for remyelination has concentrated almost exclusively on mobilization of innate OPCs. However, mature oligodendrocytes appear an important contributor to remyelination in humans. Limiting the contribution of OPC mediated repair in models of MS would allow the evaluation of remyelination-promoting agents on mature oligodendrocytes. Among remyelinating reagents reviewed, only rHIgM22 targets both OPCs and mature oligodendrocytes.

KEYWORDS:

• Remyelination
• multiple sclerosis
• Myelin
• oligodendrocyte
• progenitor cells
• clemastine
• GSK239512
• olesoxime
• Opicinumab
• clinical trials

Article highlights

• There are at least four patterns of MS pathogenesis. Two patterns (III and IV) demonstrate little remyelinating potential, which could mask therapeutic success in trials. No imaging or clinical readouts distinguish these patients.

• Remyelination in humans may be mediated via OPCs and mature oligodendrocytes. Evaluating therapeutics in preclinical models depleted of OPCs may help identify clinically relevant candidates.

• Three classes of drugs are in clinical trials for MS: small molecules, hormones, and antibodies. Hormones are furthest advanced with erythropoietin in phase III trials.

• rHIgM22 is the only agent that acts on both OPCs and oligodendrocytes. A single low dose improves myelination in acute and chronic preclinical models of demyelination.

• Because one in four MS patients are remyelination incompetent, they should be excluded from trials of potentially cytotoxic agents given the limited potential for benefit.

This box summarizes key points contained in the article.

Declaration of interest

The therapeutic human antibody rHIgM22 is owned and patented by Mayo Clinic. As inventors, AEW and MR may receive royalties if this antibody is commercialized. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

R Sutiwisesak received financial support from the Faculty of Medicine Siriraj Hospital, Mahidol University. AE Warrington was supported by Regenerative Medicine Minnesota RMM 091718 TR 011 and the Robert and Arlene Kogod Center on Aging. TC Burns was supported by NIH K12 NRDCP, NINDS NS19770, the Minnesota Partnership for Biotechnology and Genomics, Mayo Clinic Center for Regenerative Medicine, Lucius & Terrie McKelvey, Regenerative Medicine Minnesota, Humor to Fight the Tumor, Brains Together for the Cure and the Robert and Arlene Kogod Center on Aging.