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Monitoring recovery after CNS demyelination, a novel tool to de-risk pro-remyelinating strategies

In multiple sclerosis, while remarkable progress has been accomplished to control the inflammatory component of the disease, repair of demyelinated lesions is still an unmet need. Despite encouraging results generated in experimental models, several candidates favouring or promoting remyelination have not reached the expected outcomes in clinical trials. One possible reason for these failures is that, in most cases, during preclinical testing, efficacy was evaluated on histology only, while functional recovery had not been assessed. We have generated a Xenopus laevis transgenic model Tg(mbp:GFP-NTR) of conditional demyelination in which spontaneous remyelination can be accelerated using candidate molecules. Xenopus laevis is a classic model for in vivo studies of myelination because tadpoles are translucent. We reasoned that demyelination should translate into loss of sensorimotor functions followed by behavioural recovery upon remyelination. To this end, we measured the swimming speed and distance travelled before and after demyelination and during the ongoing spontaneous remyelination and have developed a functional assay based on the visual avoidance of a virtual collision. Here we show that alteration of these functional and clinical performances correlated well with the level of demyelination and that histological remyelination, assayed by counting in vivo the number of myelinating oligodendrocytes in the optic nerve, translated in clinical-functional recovery. This method was further validated in tadpoles treated with pro-remyelinating agents (clemastine, siponimod) showing that increased remyelination in the optic nerve was associated with functional improvement. Our data illustrate the potential interest of correlating histopathological parameters and functional-clinical parameters to screen molecules promoting remyelination in a simple in vivo model of conditional demyelination.

 

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The passage describes a study using a Xenopus laevis transgenic model of conditional demyelination to test candidate molecules for promoting remyelination. The authors used functional and clinical performance measures, such as swimming speed and distance, and a visual avoidance assay to assess the level of demyelination and recovery after treatment. They found that alterations in these measures correlated well with the level of demyelination and that histological remyelination translated to functional recovery. The authors also validated their method by showing that pro-remyelinating agents (clemastine, siponimod) improved remyelination and functional performance. The study suggests that evaluating functional and clinical measures in addition to histology may be a more effective way to screen molecules for promoting remyelination in vivo.

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S7179 Siponimod (BAF312) BAF312 (Siponimod) is a next-generation S1P receptor agonist, selective for S1P1 and S1P5 receptors with EC50 of 0.39 nM and 0.98 nM, exhibits >1000-fold selectivity over S1P2, S1P3 and S1P4 receptors. Phase 3.

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S1P Receptor