Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS

Abstract

ObjectiveTo identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS).MethodsBlood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range 1–7) at baseline, 6 weeks, and 15 months after the initiation of treatment with DMF (BG-12; Tecfidera). Seven healthy controls were also recruited, and blood samples were collected over the same time intervals. PBMCs were extracted from blood samples and sequenced using next-generation RNA sequencing. Treatment responders were defined using the composite outcome measure “no evidence of disease activity” (NEDA-4). Time-course and cross-sectional differential expression analyses were performed to identify transcriptomic markers of treatment response.ResultsTreatment responders (NEDA-4 positive, 8/24) over the 15-month period had 478 differentially expressed genes (DEGs) 6 weeks after the start of treatment. These were enriched for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of nuclear factor κB (NFκB) pathway transcripts. For patients who showed signs of disease activity, there were no DEGs at 6 weeks relative to their (untreated) baseline. Contrasting transcriptomes expressed at 6 weeks with those at 15 months of treatment, 0 and 1,264 DEGs were found in the responder and nonresponder groups, respectively. Transcripts in the nonresponder group (NEDA-4 negative, 18/24) were enriched for T-cell signaling genes.ConclusionShort-term PBMC transcriptome changes reflecting activation of the Nrf2 and inhibition of NFκB pathways distinguish patients who subsequently show a medium-term treatment response with DMF. Relative stabilization of gene expression patterns may accompany treatment-associated suppression of disease activity.

Omics approaches to understanding the efficacy and safety of disease-modifying treatments in multiple sclerosis

“…Cordiglieri C et al described a gene signature, that include ITGA2B, ITGB3, CD177, IGJ, IL5RA, MMP8, P2RY12, S100β genes, associated with positive response in RR-MS and drug immunomodulatory effects (Cordiglieri et al, 2016). The Gafson AR et al study showed expression changes for genes involved in Nrf2 pathway activation and NFkB pathway inhibition, which are associated with the clinical and mid-term response to dimethylfumarate (DMF) (Gafson et al, 2018). Another study, which used RNA-seq technology, indicated a different gene expression signature (FOXP3, GPI, and FCRL1), and distribution of subpopulations of lymphocytes (NK bright and plasmablasts) in Frontiers in Genetics frontiersin.org MS patients who were responsive to fingolimod compared to nonresponders.…”

“…Several studies investigating gene expression profiles in the peripheral blood of MS patients have been published. These identified peripheral gene signatures associated with both disease and its progression ( Ye et al, 2020 ) and drug response ( Hecker et al, 2013 ; De Felice et al, 2014 ; Moreno-Torres et al, 2014 ; Parnell et al, 2014 ; Cordiglieri et al, 2016 ; Gafson et al, 2018 ), as summarized in Table 3 , suggesting that gene signatures have the potential to identify individuals at risk of relapse. Ye F et al showed a five-gene signature (FTH1, GBP2, MYL6, NCOA4, SRP9) used to calculate risk scores to predict individual predicting relapse-free survival ( Ye et al, 2020 ).…”

Central stress processing, T-cell responsivity to stress hormones and disease severity in multiple sclerosis

“…Human studies addressing this question for the DMTs used in this study, however, did not report significant changes in gene expression for our genes of interest GR , FKBP5 , FKBP4 or GILZ . 66–69 Moreover, PwMS taking steroid treatment in a period of 4 weeks preceding a potential study participation were not included in the study.…”

Breaking the cycle

“…This study included a previously described cohort of patients with RRMS 14,15 separated into an initial discovery cohort and a validation cohort to test for the generalizability of results. Patients diagnosed with RRMS by the McDonald criteria 16 were recruited from the Imperial College Healthcare NHS Trust and consented for participation in the study.…”