Contributions
Abstract: P1765
Type: Poster Sessions
Abstract Category: N/A
Demyelinating lesions of the central nervous system, including those in individuals with multiple sclerosis (MS), often fail to remyelinate despite the presence of spared axons. Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that can remyelinate spared axons. We previously found that the glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and that OPCs and astrocytes within lesions express multiple hyaluronidases that digest this HA. These digestion products block OPC maturation and remyelination in rodent models of demyelination. We now report that specific bioactive sizes of HA digestion products are generated by hyaluronidases that are transcriptionally upregulated (> 2 fold) in demyelinating lesions and that these products signal through toll like receptor 4 (TLR4) via a non-canonical AKT-dependent signaling pathway. Activation of this pathway results in elevated expression of the FoxO3 transcription factor in OPCs both in vitro and in MS lesions. Interactions between FoxO3 and the Brg1 subunit of the SWI/SNF chromatin remodeling factor at myelin gene promoters results in the inhibition of myelin gene transcription. We have developed a novel small molecule hyaluronidase inhibitor that is specific for the hyaluronidase activity in demyelinating lesions. This inhibitor prevents the accumulation of bioactive HA digestion products and prevents TLR4 activation and the inhibition of myelin gene transcription. This inhibitor also accelerates OPC maturation and remyelination in lysolecithin-induced demyelinating lesions following both intracranial and intravenous injection. Furthermore, we demonstrate that this inhibitor promotes up to 60% increases in conduction velocities in demyelinating lesions, demonstrating that inhibiting hyaluronidase activity promotes functional remyelination. This novel hyaluronidase inhibitor is now being tested for its ability to promote remyelination in a pre-clinical trial utilizing a unique non-human primate model of MS at the Oregon National Primate Research Center. Our findings definitively show that specific hyaluronidases are potent therapeutic targets for treating demyelination in MS and demonstrate the feasibility of using small molecule hyaluronidase inhibitors for promoting functional remyelination.
Disclosure: L. Sherman: Supported by grants from the Congressionally Directed Medical Research Programs (MS160144), the National Multiple Sclerosis Society (RG 4843A5/1), and the National Institutes of Health (P51OD01109). S. Back: Supported by a grant from the National Institute of Neurological Disorders and Stroke (NS054044). T. Srivastava: Supported by a grant from the National Institute of Neurological Disorders and Stroke (NS054044). S. Matsumoto: Supported by grants from the Congressionally Directed Medical Research Programs (MS160144) and the National Multiple Sclerosis Society (RG 4843A5/1). F. Banine: Supported by a grant from the the National Multiple Sclerosis Society (RG 4843A5/1). W. Su: Supported by a grant from the Congressionally Directed Medical Research Programs (MS160144).
Abstract: P1765
Type: Poster Sessions
Abstract Category: N/A
Demyelinating lesions of the central nervous system, including those in individuals with multiple sclerosis (MS), often fail to remyelinate despite the presence of spared axons. Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that can remyelinate spared axons. We previously found that the glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and that OPCs and astrocytes within lesions express multiple hyaluronidases that digest this HA. These digestion products block OPC maturation and remyelination in rodent models of demyelination. We now report that specific bioactive sizes of HA digestion products are generated by hyaluronidases that are transcriptionally upregulated (> 2 fold) in demyelinating lesions and that these products signal through toll like receptor 4 (TLR4) via a non-canonical AKT-dependent signaling pathway. Activation of this pathway results in elevated expression of the FoxO3 transcription factor in OPCs both in vitro and in MS lesions. Interactions between FoxO3 and the Brg1 subunit of the SWI/SNF chromatin remodeling factor at myelin gene promoters results in the inhibition of myelin gene transcription. We have developed a novel small molecule hyaluronidase inhibitor that is specific for the hyaluronidase activity in demyelinating lesions. This inhibitor prevents the accumulation of bioactive HA digestion products and prevents TLR4 activation and the inhibition of myelin gene transcription. This inhibitor also accelerates OPC maturation and remyelination in lysolecithin-induced demyelinating lesions following both intracranial and intravenous injection. Furthermore, we demonstrate that this inhibitor promotes up to 60% increases in conduction velocities in demyelinating lesions, demonstrating that inhibiting hyaluronidase activity promotes functional remyelination. This novel hyaluronidase inhibitor is now being tested for its ability to promote remyelination in a pre-clinical trial utilizing a unique non-human primate model of MS at the Oregon National Primate Research Center. Our findings definitively show that specific hyaluronidases are potent therapeutic targets for treating demyelination in MS and demonstrate the feasibility of using small molecule hyaluronidase inhibitors for promoting functional remyelination.
Disclosure: L. Sherman: Supported by grants from the Congressionally Directed Medical Research Programs (MS160144), the National Multiple Sclerosis Society (RG 4843A5/1), and the National Institutes of Health (P51OD01109). S. Back: Supported by a grant from the National Institute of Neurological Disorders and Stroke (NS054044). T. Srivastava: Supported by a grant from the National Institute of Neurological Disorders and Stroke (NS054044). S. Matsumoto: Supported by grants from the Congressionally Directed Medical Research Programs (MS160144) and the National Multiple Sclerosis Society (RG 4843A5/1). F. Banine: Supported by a grant from the the National Multiple Sclerosis Society (RG 4843A5/1). W. Su: Supported by a grant from the Congressionally Directed Medical Research Programs (MS160144).