Glial cells as therapeutic targets in progressive multiple sclerosis

ABSTRACT

Introduction: Multiple sclerosis is a serious demyelinating disease of the central nervous system (CNS) with treatments generally restricted to immunosuppression to reduce attack rate and for symptom management. Glial cells may be useful targets for future CNS regenerative therapies to reverse disease.

Areas covered: In this review, the authors cover currently available multiple sclerosis treatments and examine potential upcoming therapies targeting glial cells. The potential for new therapeutic approaches in the treatment of progressive multiple sclerosis is examined.

Expert opinion: Microglia, astrocytes, and oligodendrocytes are each promising targets for the disease-altering treatment of multiple sclerosis. Though challenging, the opportunities presented have great potential for CNS regeneration and further investigation of glial cells in therapy is warranted. Patient-specific combinatorial therapy targeting the three glial cell types is expected to be the future of MS treatment.

KEYWORDS:

• Astrocyte
• CNS
• microglia
• multiple sclerosis
• glial cells
• oligodendrocyte
• remyelination

Article highlights

• Current MS therapies focus on immunosuppression and are unable to prevent disease progression.

• Glial cells of the CNS are promising targets for future therapies in progressive MS.

• Microglia play a dichotomous role in MS pathology, both promoting clearing of myelin debris to allow remyelination to occur and in some cases exacerbating demyelination by phagocytosis.

• Therapies targeting microglia include activation of phagocytosis to create an environment conducive to remyelination and regulation of CA/AA polarization states.

• Astrocytes play vital and, in some cases, complex regulatory roles in the CNS, making this glial cell type a complicated but potentially impactful target.

• Relatively few therapeutic approaches addressing astrocytes are under investigation, though dimethyl fumarate treatment has shown early signs of possible success.

• Oliogdendrocytes, the myelinating cells of the CNS, are strong candidates for MS therapies and exist in several states among various MS pathologies.

• Therapies to promote or enable remyelination including rHIgM22, LJM-3064, Notch1 siRNAs, and stem cell treatment appear to be the most likely avenues for successful treatment of MS.

• Significantly advanced imaging techniques are required to begin to understand individual lesion pathologies on a patient-to-patient basis.

• Empowering clinicians to identify lesion pathologies, along with the ongoing advances in treatment strategies, will enable individualized combinatorial therapy approaches in MS that may be the ultimate answer to the disease.

Acknowledgments

A clinical trial in acute MS attacks by Acorda Therapeutics regarding rHIgM22 has been completed, but data on remyelination is not yet available to the public.

Declaration of interest

rHIgM22 antibody has been licensed to Acorda Therapeutics by the Mayo Foundation, and the Mayo Clinic owns the patent for the enhancement of remyelination in MS by rHIgM22 and for the enhancement of remyelination in MS by LJM-3064. 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.