Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

Marcel J.C. Bijvelds; Floris J.M. Roos; Kelly F. Meijsen; Henk P. Roest; Monique M.A. Verstegen; Hettie M. Janssens; Luc J.W. van der Laan; Hugo R. de Jonge

doi:10.1016/j.jcf.2021.12.006

Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

Marcel J.C. Bijvelds^*, Floris J.M. Roos, Kelly F. Meijsen, Henk P. Roest, Monique M.A. Verstegen, Hettie M. Janssens, Luc J.W. van der Laan, Hugo R. de Jonge

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport. Methods: Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls. Transcriptome sequencing was performed, and bicarbonate and chloride transport were assessed in the presence or absence of ELX/IVA/TEZ, using the intestinal current measurement technique. Results: ELX/IVA/TEZ markedly enhanced bicarbonate and chloride transport across intestinal epithelium. In biliary epithelium, it failed to enhance CFTR-mediated bicarbonate transport but effectively rescued CFTR-mediated chloride transport, known to be requisite for bicarbonate secretion through the chloride-bicarbonate exchanger AE2 (SLC4A2), which was highly expressed by cholangiocytes. Biliary but not intestinal epithelial cells expressed an alternative anion channel, anoctamin-1/TMEM16A (ANO1), and secreted bicarbonate and chloride upon purinergic receptor stimulation. Conclusions: ELX/IVA/TEZ has the potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary epithelia and may counter luminal hyper-acidification in these tissues.

Original language	English
Pages (from-to)	537-543
Number of pages	7
Journal	Journal of Cystic Fibrosis
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.jcf.2021.12.006
Publication status	Published - May 2022

Bibliographical note

Funding Information:
This study was funded by the Cystic Fibrosis Foundation ( CFF-USA DEJONG16G0 ), the Fondazione Ricerca Fibrosi Cistica ( FFC#3/2016 ), the Dutch Cystic Fibrosis Foundation ( NCFS HIT-CF2 ) and the Dutch Digestive Disease Foundation ( MLDS-Diagnostiek D16–26 ).

Publisher Copyright:
© 2021 The Author(s)

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1_s2.0_S1569199321021652_mainFinal published version, 1.39 MBLicence: CC BY

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Bijvelds, M. J. C., Roos, F. J. M., Meijsen, K. F., Roest, H. P., Verstegen, M. M. A., Janssens, H. M., van der Laan, L. J. W., & de Jonge, H. R. (2022). Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers. Journal of Cystic Fibrosis, 21(3), 537-543. https://doi.org/10.1016/j.jcf.2021.12.006

@article{4db722eef0b847d4be1849316f5ed366,

title = "Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers",

abstract = "Background: In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport. Methods: Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls. Transcriptome sequencing was performed, and bicarbonate and chloride transport were assessed in the presence or absence of ELX/IVA/TEZ, using the intestinal current measurement technique. Results: ELX/IVA/TEZ markedly enhanced bicarbonate and chloride transport across intestinal epithelium. In biliary epithelium, it failed to enhance CFTR-mediated bicarbonate transport but effectively rescued CFTR-mediated chloride transport, known to be requisite for bicarbonate secretion through the chloride-bicarbonate exchanger AE2 (SLC4A2), which was highly expressed by cholangiocytes. Biliary but not intestinal epithelial cells expressed an alternative anion channel, anoctamin-1/TMEM16A (ANO1), and secreted bicarbonate and chloride upon purinergic receptor stimulation. Conclusions: ELX/IVA/TEZ has the potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary epithelia and may counter luminal hyper-acidification in these tissues.",

author = "Bijvelds, {Marcel J.C.} and Roos, {Floris J.M.} and Meijsen, {Kelly F.} and Roest, {Henk P.} and Verstegen, {Monique M.A.} and Janssens, {Hettie M.} and {van der Laan}, {Luc J.W.} and {de Jonge}, {Hugo R.}",

note = "Funding Information: This study was funded by the Cystic Fibrosis Foundation ( CFF-USA DEJONG16G0 ), the Fondazione Ricerca Fibrosi Cistica ( FFC#3/2016 ), the Dutch Cystic Fibrosis Foundation ( NCFS HIT-CF2 ) and the Dutch Digestive Disease Foundation ( MLDS-Diagnostiek D16–26 ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = may,

doi = "10.1016/j.jcf.2021.12.006",

language = "English",

volume = "21",

pages = "537--543",

journal = "Journal of Cystic Fibrosis",

issn = "1569-1993",

publisher = "Elsevier",

number = "3",

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TY - JOUR

T1 - Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

AU - Bijvelds, Marcel J.C.

AU - Roos, Floris J.M.

AU - Meijsen, Kelly F.

AU - Roest, Henk P.

AU - Verstegen, Monique M.A.

AU - Janssens, Hettie M.

AU - van der Laan, Luc J.W.

AU - de Jonge, Hugo R.

N1 - Funding Information: This study was funded by the Cystic Fibrosis Foundation ( CFF-USA DEJONG16G0 ), the Fondazione Ricerca Fibrosi Cistica ( FFC#3/2016 ), the Dutch Cystic Fibrosis Foundation ( NCFS HIT-CF2 ) and the Dutch Digestive Disease Foundation ( MLDS-Diagnostiek D16–26 ). Publisher Copyright: © 2021 The Author(s)

PY - 2022/5

Y1 - 2022/5

N2 - Background: In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport. Methods: Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls. Transcriptome sequencing was performed, and bicarbonate and chloride transport were assessed in the presence or absence of ELX/IVA/TEZ, using the intestinal current measurement technique. Results: ELX/IVA/TEZ markedly enhanced bicarbonate and chloride transport across intestinal epithelium. In biliary epithelium, it failed to enhance CFTR-mediated bicarbonate transport but effectively rescued CFTR-mediated chloride transport, known to be requisite for bicarbonate secretion through the chloride-bicarbonate exchanger AE2 (SLC4A2), which was highly expressed by cholangiocytes. Biliary but not intestinal epithelial cells expressed an alternative anion channel, anoctamin-1/TMEM16A (ANO1), and secreted bicarbonate and chloride upon purinergic receptor stimulation. Conclusions: ELX/IVA/TEZ has the potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary epithelia and may counter luminal hyper-acidification in these tissues.

AB - Background: In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport. Methods: Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls. Transcriptome sequencing was performed, and bicarbonate and chloride transport were assessed in the presence or absence of ELX/IVA/TEZ, using the intestinal current measurement technique. Results: ELX/IVA/TEZ markedly enhanced bicarbonate and chloride transport across intestinal epithelium. In biliary epithelium, it failed to enhance CFTR-mediated bicarbonate transport but effectively rescued CFTR-mediated chloride transport, known to be requisite for bicarbonate secretion through the chloride-bicarbonate exchanger AE2 (SLC4A2), which was highly expressed by cholangiocytes. Biliary but not intestinal epithelial cells expressed an alternative anion channel, anoctamin-1/TMEM16A (ANO1), and secreted bicarbonate and chloride upon purinergic receptor stimulation. Conclusions: ELX/IVA/TEZ has the potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary epithelia and may counter luminal hyper-acidification in these tissues.

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U2 - 10.1016/j.jcf.2021.12.006

DO - 10.1016/j.jcf.2021.12.006

M3 - Article

C2 - 34922851

AN - SCOPUS:85121269731

SN - 1569-1993

VL - 21

SP - 537

EP - 543

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

IS - 3

ER -

Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

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