Contributions
Abstract: P471
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Repairing mechanisms
The mechanisms underlying remyelination failure in demyelinating diseases are unclear. We previously demonstrated that the glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions from patients with multiple sclerosis (MS). The presence of HA in these lesions coincides with reactive astrogliosis and accumulation of oligodendrocyte progenitor cells (OPCs) that fail to become myelinating oligodendrocytes. The addition of HA to OPCs grown in vitro, in white matter slice cultures, or in lysolecithin-induced demyelinating lesions blocks OPC maturation and leads to remyelination failure. Interestingly, low molecular weight HA products accumulate in MS lesions. We recently reported that OPCs and reactive astrocytes within demyelinating lesions express a hyaluronidase, called PH20, that generates specific sizes of HA digestion products that inhibit OPC maturation. Blocking hyaluronidase activity promotes OPC maturation and remyelination, and restores fast conduction velocities in axons within demyelinating lesions as assessed by compound action potential recordings. Specific HA digestion products generated by PH20 block remyelination through signaling cascades shared by other inhibitors of remyelination.
We screened a number of compounds for their effects on hyaluronidase activity and have identified several novel modified flavonoids that selectively block PH20 activity and promote OPC maturation and functional remyelination of lysolecithin-induced lesions. These compounds are well tolerated in mice with experimentally induced demyelinating diseases and lead to reduced inflammatory demyelination in mice with experimental autoimmune encephalomyelitis. These compounds are currently being tested for their safety and efficacy in both rodent models and in a novel, spontaneous non-human primate model of MS, Japanese macaque encephalomyelitis, that mimics the immunological and neurohistopathological characteristics of MS in humans. All together, our data indicate that digestion products generated by hyaluronidase activity in MS lesions contribute to remyelination failure through signaling cascades shared by other mechanisms that prevent OPC maturation. Blocking hyaluronidase activity may be an effective approach to promoting functional remyelination in patients with MS.
Disclosure:
Larry S. Sherman: nothing to declare
Weiping Su: nothing to declare
Steven Matsumoto: nothing to declare
Paul Weigel: nothing to declare
Stephen Back: nothing to declare
Kesturu Girish: nothing to declare This work was supported by grant RG 4843A5/1 from the multiple sclerosis society
Abstract: P471
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Repairing mechanisms
The mechanisms underlying remyelination failure in demyelinating diseases are unclear. We previously demonstrated that the glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions from patients with multiple sclerosis (MS). The presence of HA in these lesions coincides with reactive astrogliosis and accumulation of oligodendrocyte progenitor cells (OPCs) that fail to become myelinating oligodendrocytes. The addition of HA to OPCs grown in vitro, in white matter slice cultures, or in lysolecithin-induced demyelinating lesions blocks OPC maturation and leads to remyelination failure. Interestingly, low molecular weight HA products accumulate in MS lesions. We recently reported that OPCs and reactive astrocytes within demyelinating lesions express a hyaluronidase, called PH20, that generates specific sizes of HA digestion products that inhibit OPC maturation. Blocking hyaluronidase activity promotes OPC maturation and remyelination, and restores fast conduction velocities in axons within demyelinating lesions as assessed by compound action potential recordings. Specific HA digestion products generated by PH20 block remyelination through signaling cascades shared by other inhibitors of remyelination.
We screened a number of compounds for their effects on hyaluronidase activity and have identified several novel modified flavonoids that selectively block PH20 activity and promote OPC maturation and functional remyelination of lysolecithin-induced lesions. These compounds are well tolerated in mice with experimentally induced demyelinating diseases and lead to reduced inflammatory demyelination in mice with experimental autoimmune encephalomyelitis. These compounds are currently being tested for their safety and efficacy in both rodent models and in a novel, spontaneous non-human primate model of MS, Japanese macaque encephalomyelitis, that mimics the immunological and neurohistopathological characteristics of MS in humans. All together, our data indicate that digestion products generated by hyaluronidase activity in MS lesions contribute to remyelination failure through signaling cascades shared by other mechanisms that prevent OPC maturation. Blocking hyaluronidase activity may be an effective approach to promoting functional remyelination in patients with MS.
Disclosure:
Larry S. Sherman: nothing to declare
Weiping Su: nothing to declare
Steven Matsumoto: nothing to declare
Paul Weigel: nothing to declare
Stephen Back: nothing to declare
Kesturu Girish: nothing to declare This work was supported by grant RG 4843A5/1 from the multiple sclerosis society