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

## TL;DR

This study shows that CFTR modulator therapy reduces inflammation and improves airway function in cystic fibrosis patients, but some inflammation may return over time.

## Contribution

The study provides longitudinal insights into the molecular and cellular responses of the CF airway epithelium to CFTR modulator therapy.

## Key findings

- ETI therapy led to a significant downregulation of neutrophilic inflammation genes and improved pulmonary function.
- Airway stem cell function and barrier capacity showed partial improvement at 6 months.
- Inflammatory gene expression partially returned between 6 months and 2 years, suggesting ongoing epithelial changes.

## Abstract

Elexacaftor/tezacaftor/ivacaftor (ETI) cystic fibrosis transmembrane conductance regulator (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 6 months and 2 years after ETI. The baseline to 6 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 6 months. Although clinical outcomes remained stable during the 6 month to 2 year span, transcriptional changes revealed a resurgence of baseline inflammatory programs. The time course of 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.

Longitudinal profiling of the cystic fibrosis airway epithelium reveals partially reduced inflammation, infection, and normalization of epithelial function in response to CFTR modulator therapy.