Identification of molecular pathways in distinct asthma phenotypes identified in ADEPT

A goal of the Airway Disease Endotyping for Personalized Treatment of Asthma (ADEPT) non-interventional study was to identify molecular pathways responsible for distinct asthma phenotypes. Four phenotypes (clusters 1, 2, 3, 4) based on clinical measures and patient reported outcomes were identified using medoid clustering. Cluster 3 and 4 represent the most unmet need having the lowest pulmonary function and quality of life scores despite corticorsteriod use, and while Cluster 4 was most severe, cluster 3 was least reversible while exhibiting lowest FENO and sputum eosinophilia. Microarray analysis performed on endobronchial biopsies was used to identify genes differentially expressed in cluster 3 or 4 subjects vs. healthy volunteers. From these genes, Reverse Causal Reasoning (RCR) was used to calculate probable upstream regulators and biological processes. Corticosteroid use in both clusters was readily observed by RCR. Even so, cluster 4 demonstrated greater evidence of allergic inflammation with RCR support for the transcriptional activity of GATA3 and greater expression of periostin, CCL26, and MUC5AC. In contrast, RCR suggested cluster 3 may be a remodeling endotype with support for increased TGFB1 and PDGFB and increased transcriptional activity of serum response factor and myocardin involved in smooth muscle differentiation. Determination of the endotypic features of clusters 3 and 4 will require confirmation in an independent cohort. If confirmed, alternative strategies may be envisioned in the treatment of these patient populations.