Rationale: Mepolizumab is effective for a subset of severe asthma patients in reducing exacerbation frequency. Discovery of a predictive/early marker accurately identifying patients that will have a long-term beneficial clinical response would enable targeting of treatment. Objectives: We aimed to characterise the nasal methylome and transcriptome post Mepolizumab and identify signatures related to responder/non-responder status. Methods: Nasal brushes were taken at baseline (pre-drug) and following 3 months of treatment with Mepolizumab from patients with severe asthma. Both DNA and RNA were extracted. Gene expression was investigated using poly-A RNA sequencing (25M reads) and DNA methylation analysed using the EPIC Array. Measurements and Main Results: 27 paired samples were included, 17 patients were clinical responders and 10 were non-responders at one year. Differential gene expression and DNA methylation analyses identified 6719 genes and 53 CpG sites respectively that changed in response to Mepolizumab. There were 1784 genes which were unique to responders and 893 genes unique to non-responders. Pathway analyses revealed unique gene expression signatures. Respiratory disease associations and regulators of ongoing T2 inflammation pathway were still active in non-responders, and there was an inhibition of neutrophil activation pathways in responders. Conclusions: There was a significant change in both the transcriptome and methylome in the nasal epithelium in patients three months post-Mepolizumab therapy suggesting broad effects on the airway epithelium in severe asthma. Responder and non-responder group analyses indicate there is a responder-specific gene expression profile that may aid in predicting response at one year.

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