Transcriptomic and functional responses of the cystic fibrosis airway epithelium to CFTR modulator therapy

Elexacaftor/tezacaftor/ivacaftor (ETI) CFTR modulator therapy has led to rapid and substantial improvements in cystic fibrosis (CF) airway disease. Underlying molecular and cellular mechanisms, long-term efficacy, and ability to reverse airway epithelial remodeling in established disease remain unclear. Longitudinal nasal brushes from an adult CF cohort were used to evaluate gene expression, cellular composition, stem cell function, and microbiome changes at baseline and at six months and two years after ETI. The baseline to six month span showed a massive downregulation of extensive neutrophilic inflammatory gene expression programs that correlated with increased pulmonary function and decreased sinusitis. Primary airway epithelial stem cell cultures from matched donor samples showed partially improved differentiation and barrier capacity at six months. Although clinical outcomes remained stable during the six month to two year span, transcriptional changes revealed a resurgence of baseline inflammatory programs. Time course gene expression was consistent with ongoing normalization of epithelial remodeling. Relative abundance of Pseudomonas also decreased during the time course. These data suggest that ETI rectifies inflammation, epithelial remodeling, and bacterial infection in the airways, but resurgence of inflammatory gene expression may indicate ongoing inflammation, potentially presaging disease progression with long-term therapy.