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Effect of DMF and MEF on gene expression in select mouse organs: Multi-dosing regimen

ABSTRACT: Delayed-release dimethyl fumarate (DMF) is approved in the United States, European Union, Canada, and Australia for the treatment of multiple sclerosis. DMF is also a component in a defined-mixture product with three salts of monoethyl fumarate (MEF) that is approved in Germany for the treatment of psoriasis. Characterizing common or distinct pharmacodynamic properties of DMF and MEF would provide insights into the mechanisms of action of delayed-release DMF versus fixed combination products containing DMF and MEF salts. In this study we evaluated the pharmacodynamic effects and pharmacokinetics of DMF and MEF in central nervous system and peripheral tissues of naïve mice following a single dose or 10 daily doses of DMF, MEF, or a combination of the two. DMF and MEF exhibited similar pharmacokinetic profiles, but differences were noted in biodistribution: monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited a higher degree of brain penetration, whereas MEF was preferentially partitioned into kidney. Both common and distinct pharmacodynamic responses were observed in all assessed tissues for DMF and MEF alone or in combination. These findings indicate that all fumaric acid esters cannot be considered equivalent, and combinations of compounds may exert effects not observed when agents are used individually.

ORGANISM(S): Mus musculus

PROVIDER: GSE63343 | GEO | 2020/12/10

REPOSITORIES: GEO

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Effect of DMF and MEF on gene expression in select mouse organs: Single-dosing regimen

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Project description:Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes). Responder patients to DMF exhibit a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.

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