Transcriptomic profile of multiple sclerosis patients treated with fingolimod

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical response to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA-sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (5 responders and 5 non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signalling pathways and cellular processes. These DEGs were predominantly immune-related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during fingolimod treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). These transcriptomic differences offer the potential of being exploited as biomarkers of clinical response to fingolimod. We extracted peripheral blood mononuclear cells from 10 multiple sclerosis patients immediately before starting treatment with fingolimod (basal) and at 12 months (12m) of therapy with fingolimod. Patients were classified according to their clinical response to fingolimod into responders or non-responders using the NEDA-3 status at 2 years of fingolimod therapy.