Posted January 9, 2014
Larry Sherman, Ph.D., Oregon Health & Science University, and Paul Weigel, Ph.D., Oklahoma Health Sciences Center
Multiple sclerosis (MS) is a degenerative disease of the central nervous system characterized by the destruction of myelin sheaths, which are structures that insulate nerve cell fibers for optimal conduction of electrical impulses. Over the course of the disease, MS patients progressively lose the ability to remyelinate the damaged myelin. This is due, in part, to the gradual loss of oligodendrocyte progenitor cells' (OPCs) ability to mature into myelin-producing oligodendrocytes.
In FY09, Dr. Sherman and Dr. Wiegel were awarded an MSRP Synergistic Idea Award, the intent of which is to support synergistic and multidisciplinary approaches to address a central critical problem or question in MS research. Dr. Sherman had already discovered that a high molecular form of hyaluronan (HA), one of the chief components of the extracellular matrix, accumulates in demyelinated lesions in MS patients, which led him to hypothesize that degrading the accumulated HAs via hyaluronidases (enzymes that break down HA) may promote remyelination. Unexpectedly, when the HAs were degraded in this fashion, the byproducts of some hyaluronidases prevented OPC maturation, leading Dr. Sherman to further hypothesize that specific hyaluronidases expressed in demyelinating lesions and their degradation products may be blocking OPC maturation.
With MSRP support, Dr. Sherman teamed up with Dr. Wiegel, a leading expert in the field of HA biochemistry, to assess whether OPCs in demyelinating lesions, gathered from rodents with EAE, express specific hyaluronidases and whether the byproducts of these enzymes are implicated in inhibiting OPC maturation. Results indicated that OPCs expressed several hyaluronidases, including HYAL1, HYAL2, and PH20. Interestingly, HA digestion products formed by PH20, but not the others, inhibited OPC maturation and thus prevented remyelination, signifying PH20 as a promising molecular target for promoting remyelination in MS and other demyelinating diseases. Based on these findings, Drs. Sherman and Weigel aim to identify drugs that specifically inhibit PH20 hyaluronidase activity as a potential therapeutic for promoting remyelination in MS patients.