Rodenburg, Lisa W. and Delpiano, Livia and Railean, Violeta and Centeio, Raquel and Pinto, Madalena C. and Smits, Shannon M. A. and van der Windt, Isabelle S. and van Hugten, Casper F. J. and van Beuningen, Sam F. B. and Rodenburg, Remco N. P. and van der Ent, Cornelis K. and Amaral, Margarida D. and Kunzelmann, Karl and Gray, Michael A. and Beekman, Jeffrey M. and Amatngalim, Gimano D. (2022) Drug Repurposing for Cystic Fibrosis: Identification of Drugs That Induce CFTR-Independent Fluid Secretion in Nasal Organoids. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23 (20): 12657. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)Abstract
Individuals with cystic fibrosis (CF) suffer from severe respiratory disease due to a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which impairs airway epithelial ion and fluid secretion. New CFTR modulators that restore mutant CFTR function have been recently approved for a large group of people with CF (pwCF), but similar to 19% of pwCF cannot benefit from CFTR modulators Restoration of epithelial fluid secretion through non-CFTR pathways might be an effective treatment for all pwCF. Here, we developed a medium-throughput 384-well screening assay using nasal CF airway epithelial organoids, with the aim to repurpose FDA-approved drugs as modulators of non-CFTR-dependent epithelial fluid secretion. From a similar to 1400 FDA-approved drug library, we identified and validated 12 FDA-approved drugs that induced CFTR-independent fluid secretion. Among the hits were several cAMP-mediating drugs, including beta 2-adrenergic agonists. The hits displayed no effects on chloride conductance measured in the Ussing chamber, and fluid secretion was not affected by TMEM16A, as demonstrated by knockout (KO) experiments in primary nasal epithelial cells. Altogether, our results demonstrate the use of primary nasal airway cells for medium-scale drug screening, target validation with a highly efficient protocol for generating CRISPR-Cas9 KO cells and identification of compounds which induce fluid secretion in a CFTR- and TMEM16A-indepent manner.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INTESTINAL ORGANOIDS; CHLORIDE SECRETION; TMEM16A; CLONING; CAMP; PHOSPHORYLATION; BICARBONATE; EXPRESSION; REGULATOR; MECHANISM; cystic fibrosis; nasal organoids; TMEM16A; screening assay; drug repurposing |
| Subjects: | 500 Science > 550 Earth sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2024 07:01 |
| Last Modified: | 01 Feb 2024 07:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58548 |
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