Selective S1P1/S1P5 Modulation Impacts Neurologic Architecture/Function by Protecting From Axonal Breaks and Improving Kinematic Gait in a Demyelinating Mouse Model

Identification: Conrad, Christopher


Description

Selective S1P1/S1P5 Modulation Impacts Neurologic Architecture/Function by Protecting From Axonal Breaks and Improving Kinematic Gait in a Demyelinating Mouse Model
 
C. G. Conrad*, J. V. Selkirk, M. Waseem Akhtar, M. Brand, C. Villescaz, F. L. Scott, G. J. Opiteck, K. R. Taylor Meadows
Receptos, a wholly owned subsidiary of Celgene, San Diego, CA, United States
*Corresponding Author
      
Hypothesis: Ozanimod (RPC1063), an oral, once-daily immunomodulator that selectively targets sphingosine 1-phosphate receptor 1 (S1PR1) and S1PR5, has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis. Ozanimod down-regulates S1PR1, retaining autoreactive lymphocytes in peripheral lymphoid tissues. Ozanimod also penetrates the blood-brain barrier, potentially modulating S1PR1 and S1PR5 on neural cells and preserving CNS tissue. We evaluated CNS tissue preservation by ozanimod using animal models of demyelination and mechanistic studies on primary rodent cultures. Plasma neurofilament light chain (NfL) was assessed as a potential biomarker of neurological damage.
Methods: C57BL/6 mice were concurrently treated with cuprizone (to demyelinate axons in the brain) and ozanimod (or an ozanimod surrogate, RP-101074) for 6 weeks. Motor function was assessed by kinematic gait analysis. Axonal pathology in the corpus callosum was evaluated by SMI-32 staining and presence of plasma NfL was measured. Direct activity of ozanimod on activated primary rodent astrocytes was examined in vitro.
Results: Ozanimod and RP-101074 improved functional assessment by kinematic gait and reduced swollen and transected axons in the cuprizone-induced demyelination mouse model. Plasma NfL was significantly elevated in cuprizone-treated mice over naïve controls, which was significantly reduced by RP-101074. In primary rodent astrocytes, ozanimod activated ERK and AKT signaling and attenuated release of pro-inflammatory cytokines (eg, IL-1β, TNFα) induced by LPS activation.
Conclusion: Ozanimod preserved CNS tissue through direct effects, improving functional capabilities and reducing axonal breaks in cuprizone-treated mice. Ozanimod or RP-101074 also reduced plasma NfL levels, which served as a biomarker indicative of demyelination. Neuronal preservation by ozanimod may be mediated in part by direct activity on astrocytes, attenuating their inflammatory response to a perturbed environment and maintaining a more optimal milieu for neuronal survival.  
 
Funded by Celgene Corporation
 

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