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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

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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 Gosling
Rationale: 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 Medicine

ISSN

1073-449X

Publisher

American Thoracic Society

Issue

8

Volume

201

Page range

946-954

Event location

United States

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2022-08-25

First Open Access (FOA) Date

2022-08-25

First Compliant Deposit (FCD) Date

2022-08-24