Cystic Fibrosis therapy testing using iPSCs differentiated to immature lung

Induced pluripotent, stem cell (iPSC)-derived models of airway and intestinal tissue have successfully modeled the primary defect in regulated chloride conductance caused by the major mutation, F508del and certain rare CF-causing mutations. Further, 2D and 3D epithelial tissue models have been shown to be effective in reporting the possible efficacy of interventions targeting mutant protein dysfunction. However, it remains unclear if iPSC-derived airway cultures can be used to model patient specific responses to interventions - a critical property for their future use in precision medicine. In the current work, we describe a robust, high-throughput fluorescence assay of mutant CFTR function in iPSCs differentiated to immature lung tissue. We confirm that this assay measures reproducible functional responses to modulators targeting either the major CF mutation: F508del or the rare, nonsense mutation: W1282X in five patient derived iPSC lines differentiated to immature lung. Using this assay, we show that the ranking of patient-specific responses to interventions in this stem-cell based model, recapitulates the ranking initially observed in primary nasal epithelial cultures obtained from the same individuals and studied using gold-standard bioelectric methods. In summary, we show proof of concept studies supporting the use of this novel phenotypic assay of iPSC-derived immature lung to model patient variation to therapeutic interventions and support precision medicine.