Expansion of novel therapeutics to all patients with cystic fibrosis (CF) requires personalized CFTR modulator therapy. We have developed nasospheroids, a primary cell culture-based model derived from individual CF patients and healthy subjects by a minimally invasive nasal biopsy. Confocal microscopy was utilized to measure CFTR activity by analyzing changes in cross-sectional area over time that resulted from CFTR-mediated ion and fluid movement. Both the rate of change over time and AUC were calculated. Non-CF nasospheroids with active CFTR-mediated ion and fluid movement showed a reduction in cross-sectional area, whereas no changes were observed in CF spheroids. Non-CF spheroids treated with CFTR inhibitor lost responsiveness for CFTR activation. However, nasospheroids from F508del CF homozygotes that were treated with lumacaftor and ivacaftor showed a significant reduction in cross-sectional area, indicating pharmacologic rescue of CFTR function. This model employs a simple measurement of size corresponding to changes in CFTR activity and is applicable for detection of small changes in CFTR activity from individual patients in vitro. Advancements of this technique will provide a robust model for individualized prediction of CFTR modulator efficacy.
Cell Biology; Epithelial transport of ions and water; Genetic diseases; Pulmonology.
Conflict of interest statement
Conflict of interest: M. Gentzsch, J.S. Guimbellot, N.L. Quinney, and S.E. Boyles are an inventors of the technology “airway sphere cultures as diagnostic device to monitor pharmacological responses of ion channels,” which is licensed to Path BioAnalytics. M. Gentzsch, J.S. Guimbellot, N.L. Quinney, and S.E. Boyles could receive royalties related to the license in the future. These relationships have been disclosed to and are under management by the University of North Carolina at Chapel Hill.
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