Imperial College London
Alternate

Professor Paul M. Matthews

Faculty of Medicine, Department of Brain Sciences

Edmond and Lily Safra Chair, Head of Department
 
 
 
//

Contact

 

+44 (0)20 7594 2855p.matthews

 
 
//

Assistant

 

Ms Siobhan Dillon +44 (0)20 7594 2855

 
//

Location

 

E502Burlington DanesHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Gafson:2018:10.1212/NXI.0000000000000470,
author = {Gafson, A and Kicheol, K and Cencioni, M and Van, Hecke W and Nicholas, R and Baranzini, S and Matthews, P},
doi = {10.1212/NXI.0000000000000470},
journal = {Neurology, Neuroimmunology and Neuroinflammation},
title = {Mononuclear cell transcriptome changes associated with dimethyl fumarate in multiple sclerosis.},
url = {http://dx.doi.org/10.1212/NXI.0000000000000470},
volume = {5},
year = {2018}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Objective To 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).Methods Blood 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.Results Treatment 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.Conclusion Short-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.
AU  - Gafson,A
AU  - Kicheol,K
AU  - Cencioni,M
AU  - Van,Hecke W
AU  - Nicholas,R
AU  - Baranzini,S
AU  - Matthews,P
DO  - 10.1212/NXI.0000000000000470
PY  - 2018///
SN  - 2332-7812
TI  - Mononuclear cell transcriptome changes associated with dimethyl fumarate in multiple sclerosis.
T2  - Neurology, Neuroimmunology and Neuroinflammation
UR  - http://dx.doi.org/10.1212/NXI.0000000000000470
UR  - http://hdl.handle.net/10044/1/60481
VL  - 5
ER  -
Download