Study to Test Possible Drug Target for Myelin Repair

Principal investigator Fraser J. Sim, PhD, assistant professor of pharmacology and toxicology, has received $555,000 for the project — one of three academic awards recently granted through the National Multiple Sclerosis Society’s No Opportunity Wasted campaign.

When activated, the acetylcholine muscarinic receptor type 3 gene prevents immature cells from turning into mature myelin-making cells, Sim explains.

He plans to test an M3-blocking drug already approved by the U.S. Food and Drug Administration to learn whether it can promote myelin repair in animal models of myelin disease.

Notably, his team’s experiments also will involve transplanting human cells into mice with myelin loss.

“This allows us to better model and predict whether this drug will succeed in patients with multiple sclerosis and other myelin diseases,” says Sim.

The researchers will test the drug’s ability to affect the differentiation of progenitor cells that develop into oligodendrocytes, whose membranes form the myelin sheath in the central nervous system.

In multiple sclerosis, if differentiation of these oligodendrocyte progenitor cells (OPCs) is delayed or insufficient, remyelination is limited, Sim explains. The result is axonal atrophy and irreversible neurodegeneration.

Therefore, the researchers will test their hypothesis that M3 receptor signaling in these progenitor cells regulates the timing and rate of oligodendrocyte differentiation.

“Our rationale is that these experiments will determine whether M3 is a viable pharmacological target to modify oligodendrocyte differentiation,” says Sim.

“This is important, as there are currently no known pharmacological targets capable of influencing human myelination,” Sim notes.

The research team aims to identify a specific molecular pathway that regulates oligodendrocyte differentiation and myelination in both humans and rodents.

Achieving this goal would “represent a novel and important starting point for the development of strategies aimed at enhancing myelin repair in the central nervous system,” Sim says.

Previously, Sim and his team identified a set of receptor genes, including the M3 receptor, that is expressed in both species and suggests an important role in OPC development and differentiation.

Their prior studies used a drug to activate the M3 receptor, and found it prevented oligodendrocyte differentiation. Conversely, they blocked the gene’s activation, and induced oligodendrocyte differentiation in a human culture system. Moreover, when OPCs were transplanted into a mouse model of human disease, the blocking drug increased the rate of human cell differentiation.