Does Siponimod Exert Direct Effects in the Central Nervous System?

Kipp, Markus

doi:10.3390/cells9081771

Cited by 27 publications

(27 citation statements)

References 132 publications

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“…Fingolimod is a pro-drug that needs to be activated, whereas siponimod requires no activation. Furthermore, fingolimod binds to four of the five S1P receptors, while siponimod predominantly interferes with two receptor isoforms S1PR1 and S1PR5 [ 71 ].…”

Section: Therapeutic Strategies To Stop Ms Progressionmentioning

confidence: 99%

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Geladaris

Häusler

Weber

2021

IJMS

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Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.

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Section: Therapeutic Strategies To Stop Ms Progressionmentioning

confidence: 99%

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Geladaris

Häusler

Weber

2021

IJMS

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“…Currently, only two drugs ( i.e . siponimod [Mayzent ® ] and ocrelizumab [Ocrevus ® ]) have been approved for the treatment of progressive MS [ 6 , 12 , 13 , 14 , 15 ]. In 2017, the B‐cell‐depleting drug ocrelizumab, a second‐generation humanized anti‐CD20 antibody, was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of PPMS, which has become a milestone in progressive MS therapy [ 13 ].…”

Section: Pathology Of Progressive Ms and B‐cell Targeted Therapymentioning

confidence: 99%

Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models

et al. 2021

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Ectopic lymphoid follicles (ELFs), resembling germinal centre‐like structures, emerge in a variety of infectious and autoimmune and neoplastic diseases. ELFs can be found in the meninges of around 40% of the investigated progressive multiple sclerosis (MS) post‐mortem brain tissues and are associated with the severity of cortical degeneration and clinical disease progression. Of predominant importance for progressive neuronal damage during the progressive MS phase appears to be meningeal inflammation, comprising diffuse meningeal infiltrates, B‐cell aggregates and compartmentalized ELFs. However, the absence of a uniform definition of ELFs impedes reproducible and comparable neuropathological research in this field. In this review article, we will first highlight historical aspects and milestones around the discovery of ELFs in the meninges of progressive MS patients. In the next step, we discuss how animal models may contribute to an understanding of the mechanisms underlying ELF formation. Finally, we summarize challenges in investigating ELFs and propose potential directions for future research.

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“…Ozanimod's effects in this second mouse model are likely mediated by S1P 1 . Direct CNS effects with S1P modulators are being increasingly reported in the literature (Groves et al 2013;Kipp 2020). S1P 1 is upregulated in activated astrocytes in a CPZ intoxication mouse model, and selective S1P 1 downregulation by CYM5422 significantly reduces oligodendrocyte apoptosis and activation of both astrocytes and microglia (Kim et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Deconstructing the Pharmacological Contribution of Sphingosine-1 Phosphate Receptors to Mouse Models of Multiple Sclerosis Using the Species Selectivity of Ozanimod, a Dual Modulator of Human Sphingosine 1-Phosphate Receptor Subtypes 1 and 5

Selkirk

Dines

Yan

et al. 2021

J Pharmacol Exp Ther

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Ozanimod, a sphingosine-1 phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P 1 ) and 5 (S1P 5 ), is approved for the treatment of relapsing multiple sclerosis (MS) in multiple countries. Ozanimod profiling revealed a species difference in its potency for S1P 5 in mouse, rat, and canine compared with that for human and monkey. Site-directed mutagenesis identified amino acid alanine at position 120 to be responsible for loss of activity for mouse, rat, and canine S1P 5 and mutation back to threonine as in human/monkey S1P 5 restored activity. Radioligand binding analysis performed with mouse S1P 5 confirmed the potency loss is a consequence of a loss of affinity of ozanimod for mouse S1P 5 and was restored with mutation of alanine 120 to threonine. Study of ozanimod in preclinical mouse models of MS can now determine the S1P receptor(s) responsible for observed efficacies with receptor engagement as measured using pharmacokinetic exposures of free drug. Hence, in the experimental autoimmune encephalomyelitis model, ozanimod exposures sufficient to engage S1P 1 , but not S1P 5 , resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light. In the demyelinating cuprizone model, ozanimod prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination post-intoxication. Since free drug levels in this model only engaged S1P 1, we concluded that S1P 1 activation is neuroprotective but does not appear to affect remyelination. Significance statement:Ozanimod, a selective human S1P 1/5 modulator, displays reduced potency for rodent and dog S1P 5 compared with human, which results from mutation of threonine to alanine at position 120.Ozanimod can thus be used as a selective S1P 1 agonist in mouse models of multiple sclerosis to define efficacies driven by S1P 1 but not S1P 5 . Based on readouts for experimental This article has not been copyedited and formatted. The final version may differ from this version.

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Does Siponimod Exert Direct Effects in the Central Nervous System?

Cited by 27 publications

References 132 publications

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models

Deconstructing the Pharmacological Contribution of Sphingosine-1 Phosphate Receptors to Mouse Models of Multiple Sclerosis Using the Species Selectivity of Ozanimod, a Dual Modulator of Human Sphingosine 1-Phosphate Receptor Subtypes 1 and 5

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