Transcriptomic determinants of response to biological therapy (BT) in severe uncontrolled asthma (SUA)

Response to biomarker-targeted BT in SUA is variable. The pathways involved the response are not known. We hypothesize that predictors of response can be identified in the transcriptome of responders <bold>Objective:</bold> To investigate the pathways involved in the response to BT in a population with SUA by evaluating the serum and tissue microRNA(miRNA) and messenger RNA(mRNA) profiles before and after BT <bold>Methods:</bold> Prospective study that included patients with SUA candidates for BT. Clinical variables associated to clinical response(exacerbations, use of oral corticosteroids, symptoms and lung function), and serum samples were collected prior(V1) to and 6 months after BT(V2). Bronchial biopsy(BB) was obtained in V1. Serum and tissue miRNAs were extracted and hybridized on the Affymetrix GeneChip. Tissue mRNAs were extracted and hybridized on the Clariom S Pico Assays. The change in expression between V1 and V2 in serum miRNAS was confronted to tissue expression in responders <bold>Results:</bold> 30 patients were included. A complete or partial response to BT was observed in 26 patients and no response in 4 patients. Responders showed 3 differentially expressed serum miRNAs (miR-6803-5p, miR-4281 and miR-7108-5p) and 3 tissue (miR-3689a-5p/3689b-5p and miR-3689e). These miRNAs targeted SMAD and ZBTB family genes, implicated in the negative regulation of CD4+ alpha-beta-T cell activation—biological process found to be dysregulated in serum samples. Finally we confirm the dysregulation of these family genes in BB mRNA. <bold>Conclusions:</bold> Differential expression of miRNAs implies changes in the expression of mRNAs involved in the response to BT. Changes in SMAD family genes could be a potential predictor of response to BT