CFTR modulator response measurements in subjects with cystic fibrosis using 2D differentiated nasal epithelia converted into spheroids

Cystic Fibrosis (CF) is caused by genetic defects that impair the cystic fibrosis transmembrane conductance regulator (CFTR) channel in airway epithelial cells. These defects may be overcome by specific CFTR modulating drugs, for which the efficacy can be determined in a personalized manner using 3D nasal-brushing-derived airway spheroids in a forskolin-induced swelling (FIS) assay. Despite of this, previously described culture methods and application of 3D airway spheroids in CFTR function assays have not been fully optimal. In this report we describe an alternative method of culturing nasal airway spheroids, which are derived from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture. Optimized spheroid culture conditions, enabled consistent detection of CFTR modulator responses in nasal spheroids from subjects with CF, including the highly effective CFTR triple modulator combination therapy VX-661/VX-445/VX-770.