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. 2025 Jun 5;65(6):2401855.
doi: 10.1183/13993003.01855-2024. Print 2025 Jun.

Relationship between theratyping in nasal epithelial cells and clinical outcomes in people with cystic fibrosis

Felix Ratjen  1   2   3 , Sanja Stanojevic  4 , Tarini Gunawardena  5 , Paul D W Eckford  6 , Julie Avolio  3 , Michelle Shaw  3 , Claire Bartlett  3 , Hong Ouyang  3 , Theo J Moraes  7   2   3 , Tanja Gonska  2   3   8 , Christine Bear  5
Affiliations

Relationship between theratyping in nasal epithelial cells and clinical outcomes in people with cystic fibrosis

Felix Ratjen et al. Eur Respir J. .

Abstract

Background: In people with cystic fibrosis (pwCF), human nasal epithelial cell (HNEC) cultures can be used to assess response to CF transmembrane conductance regulator (CFTR) modulators. However, thresholds of in vitro responses that predict clinical benefit remain poorly understood. In this study we describe the concordance between in vitro response in HNECs and clinical outcomes in pwCF harbouring the F508del variant, treated with either lumacaftor/ivacaftor, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor.

Methods: Response of HNECs to CFTR modulators was assessed by CFTR-mediated chloride current stimulated by forskolin or inhibited by CFTRinh-172 in both pwCF and healthy controls. Clinical response was defined as change in forced expiratory volume in 1 s (FEV1), lung clearance index (LCI), sweat chloride or respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) between baseline and within 3 months after the start of modulator treatment.

Results: In 58 unique in vitro-clinical pairs, in vitro measures of functional rescue correlated with changes in FEV1, LCI and sweat chloride, but not CFQ-R. The concordance between in vitro response and clinical outcomes was highest when a composite outcome was used. For example, an in vitro response of 10% of healthy controls had positive and negative predictive values of 90.5% and 100%, respectively, for a clinical response in either FEV1, LCI or sweat chloride.

Conclusions: We identified thresholds of nasal epithelial cell theratype response in pwCF to predict clinical benefit from CFTR modulator therapy. The utility of this therapy testing platform to predict a clinical response improves when multiple clinical outcome measures are combined.

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Conflict of interest statement

Conflict of interest: F. Ratjen reports consulting fees from Vertex Pharmaceuticals. S. Stanojevic reports support for the present study from Cystic Fibrosis Canada, grants from the American Thoracic Society, consulting fees from Chiesi Pharmaceuticals, payment or honoraria for lectures, presentations, manuscript writing or educational events from Vyaire Medical, participation on a data safety monitoring board or advisory board with Ndd Medical Technologies, leadership roles with the American Thoracic Society (Pulmonary Function Testing Committee) and European Respiratory Society (Global Lung Function Initiative), and is statistical editor for Thorax, editorial board member for the European Respiratory Journal and junior associate editor for the Canadian Journal of Respiratory, Critical Care and Sleep Medicine. P.D.W. Eckford is a paid employee of Cystic Fibrosis Canada; Cystic Fibrosis Canada partially funded this study, and has received funding from Amgen, AstraZeneca Canada, Organon, Pfizer Canada, Vertex Pharmaceuticals and Viatris. T.J. Moraes reports grants from Cystic Fibrosis Canada, SickKids Foundation, CIHR and PSI. T. Gonska reports support for the present study from SickKids Foundation and Cystic Fibrosis Canada, and grants from Vertex Pharmaceuticals. C. Bear reports support for the present study from AbbVie Pharmaceutical, grants from AbbVie Pharmaceutical, patents planned, issued or pending (US Provisional Patent Application 63/016953, Pyridazinone compounds which modulate mutant proteins for treating respiratory diseases) with The Hospital for Sick Children, and receipt of equipment, materials, drugs, medical writing, gifts or other services from AbbVie. The remaining authors have no potential conflicts of interest to disclose.

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