BOS-318 treatment enhances elexacaftor-tezacaftor-ivacaftor-mediated improvements in airway hydration and mucociliary transport.

IF 4.3 3区医学 Q1 RESPIRATORY SYSTEM

ERJ Open Research Pub Date : 2025-02-25 eCollection Date: 2025-01-01 DOI:10.1183/23120541.00445-2024

Lisa E J Douglas, James A Reihill, S Lorraine Martin

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引用次数: 0

Abstract

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.

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来源期刊

ERJ Open Research Medicine-Pulmonary and Respiratory Medicine

CiteScore

6.20

自引率

4.30%

发文量

273

审稿时长

8 weeks

期刊介绍： ERJ Open Research is a fully open access original research journal, published online by the European Respiratory Society. The journal aims to publish high-quality work in all fields of respiratory science and medicine, covering basic science, clinical translational science and clinical medicine. The journal was created to help fulfil the ERS objective to disseminate scientific and educational material to its members and to the medical community, but also to provide researchers with an affordable open access specialty journal in which to publish their work.