Image of oligodendrocyte progenitor cell (OPC)

Myelin (green) production by transplanted human oligodendrocyte progenitor cells (red) is greatly improved following the genetic block of M3R expression.

Sim Research ID’s Drug Target for Remyelination in MS

Published August 27, 2018

Research led by Fraser J. Sim, PhD, associate professor of pharmacology and toxicology, has identified a new drug target for remyelination in multiple sclerosis (MS).

“This work establishes that M3R has a functional role and if blocked, could improve myelin repair. It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients.”
Associate professor of pharmacology and toxicology

Remyelination is the spontaneous regeneration of the fatty insulator in the brain that keeps neurons communicating and has long been seen as crucial to the next big advance in treating MS.

However, a lack of understanding of how remyelination is stymied in the disease has hampered these efforts.

Muscarinic Type 3 Receptors Focus of Study

Fraser Sim

Fraser J. Sim, PhD

Sim and his fellow Jacobs School of Medicine and Biomedical Sciences researchers have found that a receptor called muscarinic type 3 (M3R), a key regulator of the remyelination process, is a promising drug target. M3R is a muscarinic receptor found on oligodendrocyte progenitor cells (OPCs), the cells that make myelin.

The finding is likely to generate some interest in the pharmaceutical world, since other muscarinic receptors have also been found to be involved in animal models of demyelinating diseases.

“Our data provide evidence that a drug targeting M3R specifically would be a useful strategy,” says Sim, senior author on the paper, in describing the research.

Genetic Approach to Blocking M3R Expression

First published in late June in The Journal of Neuroscience, the research builds on work the team published in 2015 demonstrating that MS occurs when OPCs are unable to mature and differentiate properly. They found that activation of M3R blocked differentiation of OPCs into myelin-making cells.

In that paper, the researchers reported that a drug already on the market for overactive bladder successfully inhibited that receptor, allowing for remyelination to occur in an animal model.

“That work identified solifenacin as a possible drug useful for remyelination, but we really weren’t sure which specific receptor the drug worked on,” Sim says.

Since the drug wasn’t specific to a signal receptor, he says it could produce unwanted side effects in patients.

To single out which receptor was responsible for blocking remyelination, the researchers took a genetic approach to blocking expression of M3R in both human and mouse myelin-making cells. The result was that they prevented OPCs from making M3R at all.

“This work establishes that M3R has a functional role and if blocked, could improve myelin repair,” Sim says. “It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients.”

NIH-Funded Research Seeks More Drug Targets

Sim has National Institutes of Health (NIH) funding to further understand the mechanisms of action of M3R and how it goes about impairing differentiation of myelin-making cells.

“The hope is that this will identify new and more attractive drug targets beyond M3R,” he says. “The grant also is geared toward understanding how the receptors are activated in disease. If we can understand that, then we might have another opportunity for targeting this pathway in MS.”

Funding for the research came from the following organizations:

  • Change MS Wellness Foundation
  • Empire State Stem Cell Trust Fund through the New York State Department of Health
  • Kalec Multiple Sclerosis Foundation
  • National Institute of Neurological Disorders and Stroke of the NIH
  • National Multiple Sclerosis Society
  • Skarlow Memorial Trust

2 Jacobs School Students First Authors on Paper

First authors on the paper from the Jacobs Schools are:

Co-authors from the Jacobs School are:

Other co-authors are from the following institutions:

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • University of Connecticut