Posted September 16, 2020

Larry S. Sherman, Ph.D., Oregon Health and Science University

Myelin is a substance that wraps around nerve fibers to increase the speed of nerve impulses. Myelin is damaged or destroyed in patients with multiple sclerosis (MS), an autoimmune disease, leading to motor, sensory, and cognitive impairments. Although remyelination can occur in early stages of MS, at later stages remyelination is inhibited due to the failure of oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes (OLs). Some studies have shown potential efficacy in promoting OPC maturation as a strategy to promote remyelination.

The laboratory of Dr. Larry Sherman found that the glycosaminoglycan hyaluronan (HA) accumulates in MS lesions and that it is linked to remyelination failure. With support from a Fiscal Year 2009 (FY09) MSRP Synergistic Idea Award, Dr. Sherman and collaborator Dr. Paul Wiegel (a leading expert in HA biochemistry) teamed up to assess how OPCs in demyelinating lesions in a rodent model of MS responded to HA. This work revealed that (1) OPCs expressed several hyaluronidases, enzymes that break down HA into smaller fragments, and (2) HA fragments formed by specific hyaluronidases inhibited OPC maturation thus preventing remyelination and signifying hyaluronidases as promising molecular targets for promoting remyelination in MS and other demyelinating diseases.

Building on this earlier work, and with support from an FY16 MSRP Investigator-Initiated Research Award, Dr. Sherman and his team have recently been working on developing a novel hyaluronidase inhibitor. Their goal was to test the possibility that hyaluronidase activity is directly linked to the inhibition of OPC maturation. Through this study they have characterized a novel hyaluronidase inhibitor, a modified flavonoid called S3,that blocks some but not all hyaluronidases and only inhibits other known targets of flavonoids, such as matrix metalloproteinases, at high concentrations. During their research they observed that S3 reverses HA-mediated inhibition of OPC maturation in vitro, an effect that can be overcome by excess recombinant hyaluronidase. Furthermore, they found that hyaluronidase inhibition by S3 accelerates OPC maturation in an in vitro model of white matter injury. Finally, they observed that blocking hyaluronidase activity with S3 promotes functional remyelination in mice with demyelinating lesions. Taken together, these findings support the notion that hyaluronidase activity originating from OPCs in central nervous system (CNS) lesions is sufficient to prevent OPC maturation, which delays myelination or blocks remyelination. These data also indicate that modified flavonoids can act as selective inhibitors of hyaluronidase activity and can promote OPC maturation, making them excellent candidates to accelerate myelination or promote remyelination in MS and other demyelinating conditions. 

The Sherman lab is now evaluating the potential of S3 or similar compounds in pre-clinical studies to assess their safety and efficacy in promoting remyelination. If successful, the long-term goal is to test the best of these compounds in clinical trials with MS patients and others with demyelinating diseases. 

Links:

Public and Technical Abstracts: Hyaluronan Oligosaccharides for the Promotion of Remyelination

Public and Technical Abstracts: Modified Flavonoids as Selective Inhibitors of Hyaluronidases for the Promotion of Remyelination

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