TMEM16A Potentiation A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis.pdf (1.29 MB)
TMEM16A potentiation: a novel therapeutic approach for the treatment of cystic fibrosis
journal contribution
posted on 2023-06-10, 04:30 authored by Hannah L Danahay, Sarah LilleySarah Lilley, Roy FoxRoy Fox, Holly Charlton, Juan Sabater, Brian Button, Clive McCarthy, Stephen P Collingwood, Martin GoslingRationale: Enhancing non–CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases. Objectives: To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements and Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca21-activated Cl2 channel activity and anion secretion in human bronchial epithelial (HBE) cells from patients with CF without impacting calcium signaling. ETX001 rapidly increased fluid secretion and airway surface liquid height in CF-HBE cells under both static conditions and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with CF and non-CF mucoobstructive diseases.
History
Publication status
- Published
File Version
- Published version
Journal
American Journal of Respiratory and Critical Care MedicineISSN
1073-449XPublisher
American Thoracic SocietyExternal DOI
Issue
8Volume
201Page range
946-954Event location
United StatesDepartment affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-08-25First Open Access (FOA) Date
2022-08-25First Compliant Deposit (FCD) Date
2022-08-24Usage metrics
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No categories selectedKeywords
anoctamin-1calcium-activated chloride channelmucus clearancemucus hydrationAdministrationInhalationAnimalsAnoctamin-1BronchiCalcium SignalingCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorEpithelial CellsHumansIon TransportMembrane Transport ModulatorsMucociliary ClearanceMucusPatch-Clamp TechniquesRespirationRespiratory MucosaSheepTrachea
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