A NEW study supports the clinical utility of human nasal epithelial cultures (HNECs) as predictive biomarkers for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy response in people with cystic fibrosis (pwCF) carrying the F508del variant.
Researchers evaluated the concordance between in vitro responses in HNECs and early clinical outcomes following initiation of one of three CFTR modulator combinations: Lumacaftor/Ivacaftor, Tezacaftor/Ivacaftor, or Elexacaftor/Tezacaftor/Ivacaftor. Functional rescue of CFTR was measured via chloride current stimulated by forskolin or inhibited by CFTRInh-172. These assays were conducted on nasal epithelial cells derived from both pwCF and healthy controls. Clinical endpoints were defined by change in FEV1, Lung Clearance Index (LCI), sweat chloride concentration, and the CFQ respiratory domain (CFQr), all measured within 3 months of starting therapy.
Among 58 paired in vitro-clinical datasets, CFTR-mediated chloride transport in HNECs showed significant correlation with changes in FEV1, LCI, and sweat chloride, but not with CFQr scores. Predictive accuracy improved when a composite clinical outcome was used. Notably, an in vitro response equivalent to 10% of that in healthy controls yielded a positive predictive value of 90.5% and a negative predictive value of 100% for clinical response in at least one of FEV1, LCI, or sweat chloride. These findings suggest that integrating multiple clinical endpoints increases the reliability of in vitro predictors.
This study defines a practical threshold for in vitro HNEC response that aligns with meaningful early clinical outcomes. Incorporating composite measures may improve precision in assessing CFTR modulator benefit, supporting broader use of nasal epithelial assays in personalised treatment planning for pwCF.
Reference
Ratjen F et al. Relationship between theratyping in nasal epithelial cells and clinical outcomes in people with cystic fibrosis. Eur Respir J. 2025; DOI: 10.1183/13993003.01855-2024.
