CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium

Liqun Zhang,Sherif E Gabriel,Brian Button,Susan Burkett,Raymond J Pickles,Mario H Skiadopoulos,April Mengos,Peter L Collins,Tristan Mckay,Richard C Boucher,Yan Li Dang,Yu Yan,Leatrice N Vogel

doi:10.1371/journal.pbio.1000155

Abstract

Author SummaryThe ciliated epithelium that lines the conducting airways of the lung normally functions to transport hydrated mucus secretions out of the airways to maintain respiratory sterility. Cystic fibrosis (CF) lung disease results from reduced airway surface hydration leading to decreased mucus clearance that precipitates bacterial infection and progressive obstructive lung disease. CF is a genetic disease, and the mutant protein is a chloride ion channel (CFTR) that normally regulates ion and fluid transport on the airway surface. Restoration of corrected CFTR function to the airway epithelium of CF patients by delivering a new CFTR gene to airway epithelial cells has long been envisioned as a therapeutic strategy for CF lung disease. Towards this goal, we use a novel viral vector to deliver CFTR to a culture model that represents the ciliated airway epithelium of CF patients and show that this strategy restores airway surface hydration and mucus transport to levels of that in non-CF individuals. This study demonstrates efficient and efficacious CFTR delivery to CF ciliated airway epithelium and that CFTR delivered to approximately 25% of the surface epithelial cells restores normal levels of airway surface hydration and mucus transport. These studies serve as a benchmark for the efficiency of CFTR gene delivery to CF airways for future CF gene therapy studies in vivo.

Highlights

Cystic fibrosis (CF) is the most common recessive lethal genetic disorder in Caucasian populations and results from a defect in the CFTR gene
Restoration of corrected CFTR function to the airway epithelium of CF patients by delivering a new CFTR gene to airway epithelial cells has long been envisioned as a therapeutic strategy for CF lung disease
This study demonstrates efficient and efficacious CFTR delivery to CF ciliated airway epithelium and that CFTR delivered to approximately 25% of the surface epithelial cells restores normal levels of airway surface hydration and mucus transport

Summary

Introduction

Cystic fibrosis (CF) is the most common recessive lethal genetic disorder in Caucasian populations and results from a defect in the CFTR gene. CF affects many organs, the pulmonary manifestations account for over 90% of the morbidity and mortality [1]. Dysfunction of CFTR in CF airway epithelium perturbs the normal regulation of ion transport, leading to a reduced volume of airway surface liquid (ASL), mucus dehydration, decreased mucus transport (MCT), and mucus plugging of the airways, which are hallmarks of early CF lung disease. Failure of effective mucus clearance initiates and exacerbates CF lung disease, resulting in an inability to effectively prevent or eradicate bacterial infection, typically dominated by Pseudomonas aeruginosa. Persistent neutrophil-mediated inflammation in CF airways further compromises defective clearance and, over several decades, results in airway destruction and fatal decline of lung function

Methods

Results

Discussion

Conclusion