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Circulating microRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial

ABSTRACT: Circulating microRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial

PROVIDER: PRJNA892969 | ENA |

REPOSITORIES: ENA

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Circulating microRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial

Project description:Dimethyl fumarate (DMF) is an oral drug approved for relapsing multiple sclerosis (MS) that leads to reduction of neurofilament light (NFL). This may be related to dynamics and persistence of microRNA signatures in the peripheral blood of treatment-naïve MS patients before and after dimethyl fumarate (DMF) at different time points. 210 blood samples were collected from 51 treatment-naïve patients at baseline (BL) and after 1-3, 4-7, 9-15 and 21-27 months of DMF and from 22 controls from the phase IV TREMEND trial. Using microarray, 1,085 miRNAs were two-folds above the background and compared versus NFL. Altered miRNA profiles peaked after 4-7 months. MiR-16-5p and miR-4306, involved in the NF-kB-pathway, were upregulated in low NFL samples, while miR-940 and miR-4665-3p were upregulated in high NFL samples. NFL and miRNA correlations were strongest after 4-7 months DMF. In four patients with blood samples taken at all 5 time points, time-series analysis found miR-146a-5p, the inhibitor of the NF-kB-pathway, increased 1-3 months after treatment. DMF induces dynamic changes in composite miRNA profiles 4-7 months after initiation, several involved in the NF-kB-pathway. Upregulation of miR-16-5p and miR-4306 in low-NFL, while miR-940 and miR-4665-3p in high-NFL samples may indicate a response to DMF treatment.

2022-10-26 | GSE215450 | GEO

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Illumina]

Project description:Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential in redox balance, is a target of DMF, but the precise therapeutic mechanisms remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increased the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response and suggestively associated with increased ROS generation. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

2019-07-31 | GSE130491 | GEO

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]

2019-07-31 | GSE130478 | GEO

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses

Project description:Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses

| PRJNA540471 | ENA

Transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di-(methyl fumarate) on NRF2, NF-kappaB and IRF1 pathway genes

Project description:Dimethyl fumarate (DMF) has emerged as first-line therapy for relapsing-remitting multiple scle-rosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-kappaB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-kappaB inhibition, and we confirmed IDMF-mediated NF-kappaB inhibition using a reporter assay. IDMF also down-regulated IRF1 expression and IDMF-decreased gene promoters were enriched with IRF1 recognition se-quences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates such as DRF and IDMF have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-kappaB and IRF1 contributing to mitigation of in-flammation and pyroptosis.

2022-04-27 | GSE200539 | GEO

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Illumina]

Project description:Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Illumina]

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Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]

Project description:Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis is linked with monocytic oxidative responses [Affymetrix]

| PRJNA540434 | ENA

Differential neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia

Project description:Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS) that can cross the blood-brain barrier, presenting neuroprotective potential. Its mechanism of action is not fully understood and there is a need to characterize if DMF or its bioactive metabolite monomethyl fumarate (MMF) exert neuroprotective properties. The combination of adjuvant agents such as cannabidiol (CBD) could be relevant to enhance neuroprotection. The aim of this study was to compare the effects of DMF, MMF and CBD on neuroprotective and immunomodulatory pathways in neurons and microglia in vitro. We found that DMF and CBD, but not MMF, activated the Nrf2 antioxidant pathway in neurons. Similarly, only DMF and CBD, but not MMF, prevented the LPS-induced activation of the inflammatory pathway NF-kB in microglia. However, the 3 drugs inhibited the production of nitric oxide in microglia and protected neurons against apoptosis. Transcriptomically, DMF, MMF and CBD exhibited differential effects on these pathways, with DMF achieving the most pronounced changes. Our results show that DMF and MMF, despite being structurally related, present differences in their mechanisms of action that could be relevant for the achievement of neuroprotection in MS patients and the potential of CBD as an adjuvant therapy in neuroprotection.

2024-09-30 | GSE274435 | GEO

Differential neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia [Mouse]

2024-09-30 | GSE274859 | GEO

Expression data of renal cancer cell treated with Oncolytic virus VSVd51 and Fumaric acid esters such as Dimethyl fumarate

Project description:We propose a strategy to boost the therapeutic efficacy of Oncolytic therapy by combining it with fumaric acid ester such as Dimethyl fumarate (DMF) The mechanism of action was examined by microarray analysis using the Affymetrix Human PrimeView Array.

2018-07-30 | GSE97328 | GEO

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