Schubart Wellensiek, Anna (2019) The next-generation sphingosine 1 receptor modulator BAF312 (siponimod) improves cortical network functionality in autoimmune neurodegeneration. Neural Regeneration Research, 14 (11). pp. 1950-1960. ISSN doi: 10.4103/1673-5374.259622

Abstract

Background. Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white and grey matter regions. While inflammation is present at all stages of MS, it is more pronounced in the relapsing forms of the disease (RMS), whereas progressive MS (PMS) shows significant neuroaxonal damage and grey and white matter atrophy. Hence, disease-modifying treatments beneficial in patients with RMS have limited success in PMS. BAF312 (siponimod) is a novel sphingosine 1-phosphate (S1P) receptor modulator recently shown to delay progression in PMS. It sequesters lymphocytes in the lymphoid tissues, thereby reducing CNS inflammation. Unlike most other immune-modulatory agents, BAF312 crosses the blood-brain barrier (BBB) and binds to S1P receptors on brain-resident cells like neurons, astrocytes and oligodendrocytes.
Methods. To evaluate direct neuroprotective effects of BAF312 on neuroaxonal damage, BAF312 was locally administered in the CNS of experimental autoimmune encephalomyelitis (EAE) mice with distinct grey and white matter lesions (focal EAE) using an osmotic mini-pump. Focal lesions were induced by stereotactical injection of pro-inflammatory cytokines in pre-immunized mice. The effects of intracerebral versus systemic BAF312 treatment were compared. Ex vivo flow cytometric assays were performed to investigate the effects on local inflammatory cells. Voltage-sensitive dye imaging was used to investigate the spatio-temporal patterns of neuronal network activity in cortical grey matter.
Results. Immune cell infiltration of animals with both grey and white matter lesions was lowered upon systemic administration of BAF312, while intracerebral treatment did not shift the immune phenotype. Examination of neuronal circuits with focal inflammatory lesions revealed an altered activity pattern of activation compared to controls within the cortical layers in response to electrical stimulation of white matter fiber tracts entering the cortex. BAF312 partially restored cortical neuronal circuit function.
Conclusion. Intracerebral BAF312 treatment did not influence 1 EAE disease course at the tested doses, irrespectively of the location of focal EAE lesions. However, administration of BAF312 in acute brain slices from focal EAE mice showed improvement of neuronal network functionality. The data suggest that BAF312 exerts a neuroprotective effect after crossing the BBB independently of peripheral effects on immune cells.

Item Type:	Article
Date Deposited:	24 Sep 2019 00:45
Last Modified:	24 Sep 2019 00:45
URI:	https://oak.novartis.com/id/eprint/37138