BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport
Background Cystic fibrosis transmembrane conductance regulator (CFTR) triple modulator therapy, elexacaftor–tezacaftor–ivacaftor (ETI) has transformed care for people with cystic fibrosis (CF) who have eligible mutations. It is, however, not curative. Response to treatment also varies and lung disea...
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| Format: | Article |
| Language: | English |
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European Respiratory Society
2025-02-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/11/1/00445-2024.full |
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| author | Lisa E.J. Douglas James A. Reihill S. Lorraine Martin |
| author_facet | Lisa E.J. Douglas James A. Reihill S. Lorraine Martin |
| author_sort | Lisa E.J. Douglas |
| collection | DOAJ |
| description | Background
Cystic fibrosis transmembrane conductance regulator (CFTR) triple modulator therapy, elexacaftor–tezacaftor–ivacaftor (ETI) has transformed care for people with cystic fibrosis (CF) who have eligible mutations. It is, however, not curative. Response to treatment also varies and lung disease, although slowed, remains progressive. We have previously demonstrated inhibition of the epithelial sodium channel (ENaC) by selective furin inhibition to be an alternative, mutation-agnostic approach that can enhance airways hydration and restore mucociliary transport (MCT) in CF. Inhibition of furin therefore, offers a potential therapeutic strategy for those ineligible, intolerant or nonresponsive to ETI and may provide a further opportunity for clinical benefit for those currently treated with ETI. The aim of this study was to determine the impact of furin inhibition on ETI responses to assess its utility as an adjunct therapy.
Methods
Differentiated primary CF human bronchial epithelial cells (HBECs) were treated with the highly selective furin inhibitor BOS-318 and with ETI. Ion channel function was measured using a 24-channel Transepithelial Current Clamp (TECC-24) system and airways surface hydration was investigated by measuring airway surface liquid (ASL) height and MCT rate.
Results
The presence of BOS-318 had no effect on the ability of ETI to stimulate CFTR-mediated Cl− secretion but contributed a reduced Na+ transport via robust inhibition of ENaC. This altered ion transport profile effected an improved ASL height and MCT rate, which were significantly greater than improvements observed with ETI alone, demonstrating the benefits of the dual approach.
Conclusions
Selective furin inhibition has the potential to further improve clinical outcomes for all people with CF and offers opportunity as an adjunct to improve responses to currently available CFTR modulator therapies. |
| format | Article |
| id | doaj-art-8ffccdd7273843379eb8a6feca66a443 |
| institution | DOAJ |
| issn | 2312-0541 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj-art-8ffccdd7273843379eb8a6feca66a4432025-08-20T03:16:36ZengEuropean Respiratory SocietyERJ Open Research2312-05412025-02-0111110.1183/23120541.00445-202400445-2024BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transportLisa E.J. Douglas0James A. Reihill1S. Lorraine Martin2 School of Pharmacy, Queen's University Belfast, Belfast, UK School of Pharmacy, Queen's University Belfast, Belfast, UK School of Pharmacy, Queen's University Belfast, Belfast, UK Background Cystic fibrosis transmembrane conductance regulator (CFTR) triple modulator therapy, elexacaftor–tezacaftor–ivacaftor (ETI) has transformed care for people with cystic fibrosis (CF) who have eligible mutations. It is, however, not curative. Response to treatment also varies and lung disease, although slowed, remains progressive. We have previously demonstrated inhibition of the epithelial sodium channel (ENaC) by selective furin inhibition to be an alternative, mutation-agnostic approach that can enhance airways hydration and restore mucociliary transport (MCT) in CF. Inhibition of furin therefore, offers a potential therapeutic strategy for those ineligible, intolerant or nonresponsive to ETI and may provide a further opportunity for clinical benefit for those currently treated with ETI. The aim of this study was to determine the impact of furin inhibition on ETI responses to assess its utility as an adjunct therapy. Methods Differentiated primary CF human bronchial epithelial cells (HBECs) were treated with the highly selective furin inhibitor BOS-318 and with ETI. Ion channel function was measured using a 24-channel Transepithelial Current Clamp (TECC-24) system and airways surface hydration was investigated by measuring airway surface liquid (ASL) height and MCT rate. Results The presence of BOS-318 had no effect on the ability of ETI to stimulate CFTR-mediated Cl− secretion but contributed a reduced Na+ transport via robust inhibition of ENaC. This altered ion transport profile effected an improved ASL height and MCT rate, which were significantly greater than improvements observed with ETI alone, demonstrating the benefits of the dual approach. Conclusions Selective furin inhibition has the potential to further improve clinical outcomes for all people with CF and offers opportunity as an adjunct to improve responses to currently available CFTR modulator therapies.http://openres.ersjournals.com/content/11/1/00445-2024.full |
| spellingShingle | Lisa E.J. Douglas James A. Reihill S. Lorraine Martin BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport ERJ Open Research |
| title | BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport |
| title_full | BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport |
| title_fullStr | BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport |
| title_full_unstemmed | BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport |
| title_short | BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport |
| title_sort | bos 318 treatment enhances elexacaftor tezacaftor ivacaftor mediated improvements in airway hydration and mucociliary transport |
| url | http://openres.ersjournals.com/content/11/1/00445-2024.full |
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