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| Item Type: | Article |
|---|---|
| Title: | High-throughput screening for modulators of CFTR activity based on genetically engineered cystic fibrosis disease-specific iPSCs |
| Creators Name: | Merkert, S., Schubert, M., Olmer, R., Engels, L., Radetzki, S., Veltman, M., Scholte, B.J., Zöllner, J., Pedemonte, N., Galietta, L.J.V., von Kries, J.P. and Martin, U. |
| Abstract: | 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. |
| Keywords: | Cystic Fibrosishuman iPSCs, Genome Engineering by TALENs, CFTR, High-Throughput Drug Screening, Halide-Sensitive eYFP, Differentiation to Intestinal Epithelia |
| Source: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 12 |
| Number: | 6 |
| Page Range: | 1389-1403 |
| Date: | 11 June 2019 |
| Official Publication: | https://doi.org/10.1016/j.stemcr.2019.04.014 |
| PubMed: | View item in PubMed |
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