Contributions
Abstract: EP1609
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Ozanimod (RPC1063) selectively targets S1P1R and S1P5R and has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis (RMS). S1P1R and S1P5R expression on T and B cells as well as glial cells provides a series of critical control points by which ozanimod can disrupt the inflammatory cascade of MS. Furthermore, ozanimod penetrates the blood-brain barrier and potentially promotes CNS-tissue preservation. Neurofilament light chain (NfL) is released into the cerebrospinal fluid and serum/plasma following axonal injury and degeneration. It may serve as a biomarker for monitoring neurological damage in RMS.
Methods: The concentration of NfL was measured in the plasma of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination mouse models. Blood was isolated from mice via terminal cardiac puncture and plasma NfL was measured at Quanterix (Lexington, MA) using the Simoa technology platform. In EAE, mice were therapeutically dosed with ozanimod for 14 days and then spinal cords were assessed for inflammation by H&E staining and demyelination by Luxol Fast Blue at termination. In the cuprizone model, mice were treated with an ozanimod surrogate (RP-101074) for six weeks concurrently with cuprizone and corpus callosum sections at termination were stained with SMI-32 to evaluate neuronal breaks.
Results: Plasma NfL was significantly elevated in EAE and cuprizone-treated mice over naïve controls. Elevated plasma NfL levels correlated with spinal cord inflammation and demyelination in EAE and with neuronal breaks in the corpus callosum of mice treated with cuprizone. Ozanimod treatment in EAE significantly reduced plasma NfL levels correlating with a significant reduction in clinical scores and spinal cord inflammation and demyelination. Mice treated with RP-101074 in the cuprizone model had significantly reduced plasma NfL and neuronal breaks, supportive of a neuroprotective effect.
Conclusion: Plasma NfL was significantly elevated in EAE mice and in the cuprizone-treated mice compared to naïve, non-diseased induced animals. Elevated plasma NfL correlated with clinical scores and spinal cord inflammation and demyelination in EAE as well as with neuronal breaks in the cuprizone model. In both of these preclinical studies, plasma NfL served as a biomarker indicative of CNS injury, inflammation and demyelination. These observed effects indicate a potential positive and direct CNS effect of ozanimod.
Disclosure:
K. R. Taylor Meadows, Shareholder: Celgene.
F. L. Scott, Shareholder: Celgene.
C. Villescaz, Sharholder: Celgene.
B. Clemons, Shareholder: Celgene.
C. Lopez, Shareholder: Celgene.
S. Sawa-Ballweber, Shareholder: Celgene.
K. Dines, Shareholder: Celgene.
G. J. Opiteck, Shareholder: Celgene.
Abstract: EP1609
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Ozanimod (RPC1063) selectively targets S1P1R and S1P5R and has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis (RMS). S1P1R and S1P5R expression on T and B cells as well as glial cells provides a series of critical control points by which ozanimod can disrupt the inflammatory cascade of MS. Furthermore, ozanimod penetrates the blood-brain barrier and potentially promotes CNS-tissue preservation. Neurofilament light chain (NfL) is released into the cerebrospinal fluid and serum/plasma following axonal injury and degeneration. It may serve as a biomarker for monitoring neurological damage in RMS.
Methods: The concentration of NfL was measured in the plasma of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination mouse models. Blood was isolated from mice via terminal cardiac puncture and plasma NfL was measured at Quanterix (Lexington, MA) using the Simoa technology platform. In EAE, mice were therapeutically dosed with ozanimod for 14 days and then spinal cords were assessed for inflammation by H&E staining and demyelination by Luxol Fast Blue at termination. In the cuprizone model, mice were treated with an ozanimod surrogate (RP-101074) for six weeks concurrently with cuprizone and corpus callosum sections at termination were stained with SMI-32 to evaluate neuronal breaks.
Results: Plasma NfL was significantly elevated in EAE and cuprizone-treated mice over naïve controls. Elevated plasma NfL levels correlated with spinal cord inflammation and demyelination in EAE and with neuronal breaks in the corpus callosum of mice treated with cuprizone. Ozanimod treatment in EAE significantly reduced plasma NfL levels correlating with a significant reduction in clinical scores and spinal cord inflammation and demyelination. Mice treated with RP-101074 in the cuprizone model had significantly reduced plasma NfL and neuronal breaks, supportive of a neuroprotective effect.
Conclusion: Plasma NfL was significantly elevated in EAE mice and in the cuprizone-treated mice compared to naïve, non-diseased induced animals. Elevated plasma NfL correlated with clinical scores and spinal cord inflammation and demyelination in EAE as well as with neuronal breaks in the cuprizone model. In both of these preclinical studies, plasma NfL served as a biomarker indicative of CNS injury, inflammation and demyelination. These observed effects indicate a potential positive and direct CNS effect of ozanimod.
Disclosure:
K. R. Taylor Meadows, Shareholder: Celgene.
F. L. Scott, Shareholder: Celgene.
C. Villescaz, Sharholder: Celgene.
B. Clemons, Shareholder: Celgene.
C. Lopez, Shareholder: Celgene.
S. Sawa-Ballweber, Shareholder: Celgene.
K. Dines, Shareholder: Celgene.
G. J. Opiteck, Shareholder: Celgene.