Gene expression and DNA methylation changes induced by Mepolizumab in the nasal epithelium in severe asthma

Abstract

Background: Mepolizumab, an anti-IL5 monoclonal antibody therapy, can reduce steroid burden and is effective for a subset of severe asthma patients in reducing exacerbation frequency. Currently, there is a lack of understanding of the effects on the airway epithelium, including the nasal transcriptomic or DNA methylation profile and downstream pathways.

Objectives: To investigate changes in gene expression and/or DNA methylation profiles in nasal epithelium of severe asthma patients after 3 months of Mepolizumab treatment.

Methods: Nasal epithelial brushes were taken at baseline (pre-drug) and at 3 months of Mepolizumab treatment for 29 patients (part of the Investigating Poor Response to Monoclonal therapy in Asthma study). Both DNA and RNA was extracted from the same sample. Gene expression was investigated using Illumina dual stranded poly-A RNA sequencing (25 M reads) and DNA methylation was examined using the EPIC Array. Differential gene expression was determined using software packages in RStudio. Pathway analysis was carried out in IPA.

Results: Differential analyses identified 6719 genes (2547 down- and 4172 up-regulated) and 53 CpG sites that change in response to Mepolizumab therapy. 42 of the differentially methylated CpG sites were correlated with 838 of the differentially expressed genes. Pathway analyses identified TNF-alpha as a key inhibited upstream regulator and changes in Type 1 and 2 inflammation. Other significant pathways included airway remodelling and cilia function.

Conclusion: Mepolizumab induces significant changes in both the transcriptome and methylome in the nasal epithelium in severe asthma patients, including changes in the inflammatory profile.