Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis
transmembrane conductance regulator anion channel, resulting in significant morbidity and
mortality. The progress in elucidating the role of CFTR using established animal and cellbased
models led to the recent discovery of effective modulators for most individuals with CF.
However, a subset of individuals with CF do not respond to these modulators and there is an
urgent need to develop novel therapeutic strategies. In this study, we generate a panel of
airway epithelial cells using induced pluripotent stem cells from individuals with common or
rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure
CFTR function we adapt two established in vitro assays for use in induced pluripotent stem
cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as
well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect
genotype-specific differences in CFTR baseline function and response to CFTR modulators.
These results demonstrate the potential of the human induced pluripotent stem cell platform
as a research tool to study CF and in particular accelerate therapeutic development for CF
caused by rare variants.
