High-throughput screening for modulators of CFTR activity based on genetically engineered cystic fibrosis disease-specific iPSCs


  • S. Merkert
  • M. Schubert
  • R. Olmer
  • L. Engels
  • S. Radetzki
  • M. Veltman
  • B.J. Scholte
  • J. Zöllner
  • N. Pedemonte
  • L.J.V. Galietta
  • J.P. von Kries
  • U. Martin


  • Stem Cell Reports


  • Stem Cell Reports 12 (6): 1389-1403


  • Organotypic culture systems from disease-specific induced pluripotent stem cells (iPSCs) exhibit obvious advantages compared with immortalized cell lines and primary cell cultures, but implementation of iPSC-based high-throughput (HT) assays is still technically challenging. Here, we demonstrate the development and conduction of an organotypic HT Cl(-)/I(-) exchange assay using cystic fibrosis (CF) disease-specific iPSCs. The introduction of a halide-sensitive YFP variant enabled automated quantitative measurement of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function in iPSC-derived intestinal epithelia. CFTR function was partially rescued by treatment with VX-770 and VX-809, and seamless gene correction of the p.Phe508del mutation resulted in full restoration of CFTR function. The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of ∼42,500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modeling can also be utilized for drug screening in a true HT format.