Nasal epithelial cell culture FRAP predicts cystic fibrosis therapeutic response

Human nasal epithelial (HNE) cells can be sampled non-invasively and cultured to provide a model of the airway epithelium that reflects cystic fibrosis (CF) pathophysiology. We hypothesized thatin vitromeasures of HNE cell physiology would correlate directly within vivomeasures of lung physiology and therapeutic response, providing a framework for using HNEs for therapeutic development and precision medicine. We sampled nasal cells from participants with CF (CF, n=26), healthy controls (HC, n=14), and the single mutation carrier parents of the CF group (CR, n=16). Participants underwent lung physiology and sweat chloride testing, and nuclear imaging-based measurement of mucociliary clearance (MCC) and small-molecule absorption (ABS). CF participants completed a second imaging day that included hypertonic saline (HS) inhalation to assess therapeutic response in terms of MCC. HNE measurements included Ussing chamber electrophysiology, small molecule and liquid absorption rates, and particle diffusion rates through the HNE airway surface liquid measured using fluorescence recovery after photobleaching (FRAP). Long FRAP diffusion times were associated with increased MCC response to HS in CF. This implies a strong relationship between inherent factors affecting ASL mucin concentration and therapeutic response to a hydrating therapy. MCC decreased with age in the CR group which had a larger range of ages than the other two groups. Likely this indicates a general age-related effect that may be accentuated in this group. Measures of lung ABS correlated with sweat chloride in both the HC and CF groups indicating that CFTR function drives this measure of paracellular small-molecule probe absorption.