Presentation Title

The Sphingosine 1-phosphate (S1P) receptor modulator, Baf312 decreases oligodendrocyte death and axon demyelination in a mouse model of Multiple Sclerosis

Start Date

November 2016

End Date

November 2016

Location

HUB 302-#66

Type of Presentation

Poster

Abstract

The purpose of this study is to investigate the therapeutic effects of sphingosine 1-phosphate (S1P) receptor modulator, Baf312, to inhibit axonal demyelination and degeneration in the cuprizone mouse model of multiple sclerosis (MS). Multiple sclerosis is a neurodegenerative, demyelinating, inflammatory disease of the central nervous system that currently has no cure, but is commonly treated with (SP1) antagonist Fingolimod. Baf312 is a second generation bioactive sphingolipid selective for S1P1 and S1P5 receptors. The ability of Baf312 to cross the blood brain barrier permits its interaction with S1P receptors on glial cells in the CNS; whereas in the PNS, S1P1 receptors are essential for lymphocyte egress from lymph nodes. In 2016 Phase III EXPAND study by Novartis Pharmaceuticals AG, Baf312 has been shown to reduce the risk of disability progression by 21%. Baf312 (0.11mg/kg) or vehicle (0.1mL of 1% carboxymethylcellulose) was administered to age and sex matched C57BL/6 mice by daily oral gavage during DM (4.5week CPZ) or RM periods (3weeks normal diet, following DM). Results were assessed, in part, by immunohistochemistry (IHC) of myelin proteins and inflammatory markers in the corpus callosum (CC). The CC is the largest white matter structure of the brain, responsible for facilitating crosstalk between the two hemispheres. During DM, significant results were seen by a 30 percent decrease in the loss of myelin protein intensity with Baf312 treatment, along with a 20 percent decrease in axonal damage. The lymphocyte marker CD45 and macrophage marker CD11b were unchanged, overall, whereas GFAP—a marker for astrocytes also indicating some degree of morphological reactivity, was significantly decreased in Baf312 treated groups, compared to DM. These findings support a significant role for Baf312 in protecting axons during chronic demyelination periods, which could be critical for ameliorating symptoms during relapses and periods of progressive demyelination in MS patients.

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The Sphingosine 1-phosphate (S1P) receptor modulator, Baf312 decreases oligodendrocyte death and axon demyelination in a mouse model of Multiple Sclerosis

HUB 302-#66

The purpose of this study is to investigate the therapeutic effects of sphingosine 1-phosphate (S1P) receptor modulator, Baf312, to inhibit axonal demyelination and degeneration in the cuprizone mouse model of multiple sclerosis (MS). Multiple sclerosis is a neurodegenerative, demyelinating, inflammatory disease of the central nervous system that currently has no cure, but is commonly treated with (SP1) antagonist Fingolimod. Baf312 is a second generation bioactive sphingolipid selective for S1P1 and S1P5 receptors. The ability of Baf312 to cross the blood brain barrier permits its interaction with S1P receptors on glial cells in the CNS; whereas in the PNS, S1P1 receptors are essential for lymphocyte egress from lymph nodes. In 2016 Phase III EXPAND study by Novartis Pharmaceuticals AG, Baf312 has been shown to reduce the risk of disability progression by 21%. Baf312 (0.11mg/kg) or vehicle (0.1mL of 1% carboxymethylcellulose) was administered to age and sex matched C57BL/6 mice by daily oral gavage during DM (4.5week CPZ) or RM periods (3weeks normal diet, following DM). Results were assessed, in part, by immunohistochemistry (IHC) of myelin proteins and inflammatory markers in the corpus callosum (CC). The CC is the largest white matter structure of the brain, responsible for facilitating crosstalk between the two hemispheres. During DM, significant results were seen by a 30 percent decrease in the loss of myelin protein intensity with Baf312 treatment, along with a 20 percent decrease in axonal damage. The lymphocyte marker CD45 and macrophage marker CD11b were unchanged, overall, whereas GFAP—a marker for astrocytes also indicating some degree of morphological reactivity, was significantly decreased in Baf312 treated groups, compared to DM. These findings support a significant role for Baf312 in protecting axons during chronic demyelination periods, which could be critical for ameliorating symptoms during relapses and periods of progressive demyelination in MS patients.