Looking into the future: experimental studies of new therapiesFriday, October 04, 2013, 15:16 - 15:28
Targeting the PH20 hyaluronidase to promote functional remyelinationL. Sherman, W. Su, F. Banine, S. Foster, S. Matsumoto, P. Weigel, S. Back, M. Preston (Beaverton, US)
Demyelination is a significant cause of debilitation in patients with multiple sclerosis (MS). The inhibition of oligodendrocyte progenitor cell (OPC) maturation in demyelinated lesions is an underlying cause of remyelination failure. Thus, defining strategies to promote OPC maturation is an important aim in the development of therapies that reverse MS disability. We found that high molecular weight forms (HMW; around 1 million Da) of the glycosaminoglycan hyaluronan (HA) accumulate in demyelinating lesions in patients with MS, in mice with experimental autoimmune encephalomyelitis and in Japanese macaques with a spontaneous MS-like disease (Nat. Med. 11(9):966-72 and unpublished findings). This HA is synthesized predominantly by reactive astrocytes. Adding HMW HA to demyelinated lesions inhibits OPC maturation and remyelination. Our group and others subsequently discovered that OPCs and reactive astrocytes within demyelinating lesions express hyaluronidases that digest HA. We found that HA digestion products generated by one of these enzymes, called PH20, blocks OPC maturation and remyelination (Ann. Neurol. 73(2):266-80). We now show that only products between 100,000 and 500,000 Da have this activity. These data support the hypothesis that the HMW HA generated by reactive astrocytes is digested by PH20 expressed within demyelinating lesions, and that PH20-generated digestion products of HA block OPC maturation and remyelination. We postulated that inhibiting PH20 activity would promote OPC maturation and remyelination. Consistent with this hypothesis, blocking HA synthesis in OPC cultures with the hyaluronan synthase inhibitor 4-methylumbelliferone has no affect on OPC maturation, while pharmacologic inhibition of hyaluronidase activity using L-ascorbic acid 6-hexadecanoate (VCPAL) promotes OPC maturation and remyelination in mice with chemically-induced demyelinating corpus callosum lesions. Furthermore, using compound action potential recordings, we found that VCPAL increased the conduction velocities of axons in these remyelinating lesions. All together, these data indicate that blocking PH20 activity may be an efficacious strategy to promote remyelination. We are currently evaluating a number of alternative novel agents that specifically target PH20 activity for their ability to promote OPC maturation. Given that PH20 is not normally expressed in the brain, we predict that these agents will promote remyelination with limited side effects.
Funded by the NIH, DOD, and NMSS.
Nothing to disclose