Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells

Abstract Cystic fibrosis (CF) is a genetic disease characterized by CF transmembrane regulator (CFTR) dysfunction. With over 2000 CFTR variants identified, in addition to known patient to patient variability, there is a need for personalized treatment. The discovery of CFTR modulators has shown effi...

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Autores principales:	Jenny P. Nguyen, Matthew Bianca, Ryan D. Huff, Nicholas Tiessen, Mark D. Inman, Jeremy A. Hirota
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c43889b243f642f6859763737637b9d6
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spelling	oai:doaj.org-article:c43889b243f642f6859763737637b9d62021-12-02T14:01:37ZModulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells10.1038/s41598-020-79555-w2045-2322https://doaj.org/article/c43889b243f642f6859763737637b9d62021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79555-whttps://doaj.org/toc/2045-2322Abstract Cystic fibrosis (CF) is a genetic disease characterized by CF transmembrane regulator (CFTR) dysfunction. With over 2000 CFTR variants identified, in addition to known patient to patient variability, there is a need for personalized treatment. The discovery of CFTR modulators has shown efficacy in certain CF populations, however there are still CF populations without valid therapeutic options. With evidence suggesting that single drug therapeutics are insufficient for optimal management of CF disease, there has been an increased pursuit of combinatorial therapies. Our aim was to test cyclic AMP (cAMP) modulation, through ATP Binding Cassette Transporter C4 (ABCC4) and phosphodiesterase-4 (PDE-4) inhibition, as a potential add-on therapeutic to a clinically approved CFTR modulator, VX-770, as a method for increasing CFTR activity. Human airway epithelial cells (Calu-3) were used to test the efficacy of cAMP modulation by ABCC4 and PDE-4 inhibition through a series of concentration–response studies. Our results showed that cAMP modulation, in combination with VX-770, led to an increase in CFTR activity via an increase in sensitivity when compared to treatment of VX-770 alone. Our study suggests that cAMP modulation has potential to be pursued as an add-on therapy for the optimal management of CF disease.Jenny P. NguyenMatthew BiancaRyan D. HuffNicholas TiessenMark D. InmanJeremy A. HirotaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jenny P. Nguyen Matthew Bianca Ryan D. Huff Nicholas Tiessen Mark D. Inman Jeremy A. Hirota Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells
description	Abstract Cystic fibrosis (CF) is a genetic disease characterized by CF transmembrane regulator (CFTR) dysfunction. With over 2000 CFTR variants identified, in addition to known patient to patient variability, there is a need for personalized treatment. The discovery of CFTR modulators has shown efficacy in certain CF populations, however there are still CF populations without valid therapeutic options. With evidence suggesting that single drug therapeutics are insufficient for optimal management of CF disease, there has been an increased pursuit of combinatorial therapies. Our aim was to test cyclic AMP (cAMP) modulation, through ATP Binding Cassette Transporter C4 (ABCC4) and phosphodiesterase-4 (PDE-4) inhibition, as a potential add-on therapeutic to a clinically approved CFTR modulator, VX-770, as a method for increasing CFTR activity. Human airway epithelial cells (Calu-3) were used to test the efficacy of cAMP modulation by ABCC4 and PDE-4 inhibition through a series of concentration–response studies. Our results showed that cAMP modulation, in combination with VX-770, led to an increase in CFTR activity via an increase in sensitivity when compared to treatment of VX-770 alone. Our study suggests that cAMP modulation has potential to be pursued as an add-on therapy for the optimal management of CF disease.
format	article
author	Jenny P. Nguyen Matthew Bianca Ryan D. Huff Nicholas Tiessen Mark D. Inman Jeremy A. Hirota
author_facet	Jenny P. Nguyen Matthew Bianca Ryan D. Huff Nicholas Tiessen Mark D. Inman Jeremy A. Hirota
author_sort	Jenny P. Nguyen
title	Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells
title_short	Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells
title_full	Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells
title_fullStr	Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells
title_full_unstemmed	Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells
title_sort	modulation of camp metabolism for cftr potentiation in human airway epithelial cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c43889b243f642f6859763737637b9d6
work_keys_str_mv	AT jennypnguyen modulationofcampmetabolismforcftrpotentiationinhumanairwayepithelialcells AT matthewbianca modulationofcampmetabolismforcftrpotentiationinhumanairwayepithelialcells AT ryandhuff modulationofcampmetabolismforcftrpotentiationinhumanairwayepithelialcells AT nicholastiessen modulationofcampmetabolismforcftrpotentiationinhumanairwayepithelialcells AT markdinman modulationofcampmetabolismforcftrpotentiationinhumanairwayepithelialcells AT jeremyahirota modulationofcampmetabolismforcftrpotentiationinhumanairwayepithelialcells
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Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells

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