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Drug Repurposing for Cystic Fibrosis: Identification of Drugs That Induce CFTR-Independent Fluid Secretion in Nasal Organoids

Lookup NU author(s): Livia Delpiano, Dr Michael Gray

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 ~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 ~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 β2-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.


Publication metadata

Author(s): Rodenburg LW, Delpiano L, Railean V, Centeio R, Pinto MC, Smits SMA, van der Windt IS, van Hugten CFJ, van Beuningen SFB, Rodenburg RNP, van der Ent CK, Amaral MD, Kunzelmann K, Gray MA, Beekman JM, Amatngalim GD

Publication type: Article

Publication status: Published

Journal: International Journal of Molecular Sciences

Year: 2022

Volume: 23

Issue: 20

Online publication date: 21/10/2022

Acceptance date: 18/10/2022

Date deposited: 07/11/2022

ISSN (electronic): 1422-0067

Publisher: MDPI

URL: https://doi.org/10.3390/ijms232012657

DOI: 10.3390/ijms232012657

PubMed id: 36293514


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Funding

Funder referenceFunder name
UIDP/04046/2020
SRC013
UIDB/04046/2020

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