TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis

Overview

Journal Am J Respir Crit Care Med

Specialty Critical Care

Date 2020 Jan 4

PMID 31898911

Citations 43

Authors

Henry L Danahay

Sarah Lilley

Roy Fox

Holly Charlton

Juan Sabater

Brian Button

Clive McCarthy

Stephen P Collingwood

Martin Gosling

Affiliations

Soon will be listed here.

Abstract

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. To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. 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. Potentiating the activity of TMEM16A with ETX001 increased the Ca-activated Cl 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. 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.

Citing Articles

Tamsulosin ameliorates bone loss by inhibiting the release of Cl through wedging into an allosteric site of TMEM16A.

Li S, Sun W, Li S, Zhu L, Guo S, He J Proc Natl Acad Sci U S A. 2024; 122(1):e2407493121.

PMID: 39739807 PMC: 11725887. DOI: 10.1073/pnas.2407493121.

The Tmem16a chloride channel is required for mucin maturation after secretion from goblet-like cells in the Xenopus tropicalis tadpole skin.

Dubaissi E, Hilton E, Lilley S, Collins R, Holt C, March P Sci Rep. 2024; 14(1):25555.

PMID: 39461969 PMC: 11514049. DOI: 10.1038/s41598-024-76482-y.

Cystic fibrosis.

Mall M, Burgel P, Castellani C, Davies J, Salathe M, Taylor-Cousar J Nat Rev Dis Primers. 2024; 10(1):53.

PMID: 39117676 DOI: 10.1038/s41572-024-00538-6.

TMEM16 proteins: Ca‑activated chloride channels and phospholipid scramblases as potential drug targets (Review).

Huang Z, Iqbal Z, Zhao Z, Chen X, Mahmmod A, Liu J Int J Mol Med. 2024; 54(4).

PMID: 39092585 PMC: 11315658. DOI: 10.3892/ijmm.2024.5405.

Benzbromarone as adjuvant therapy for cystic fibrosis lung disease: a pilot clinical trial.

Friedrich F, Petry L, Garcia L, Pieta M, Meneses A, Bittencourt L J Bras Pneumol. 2024; 50(3):e20230292.

PMID: 38896732 PMC: 11449610. DOI: 10.36416/1806-3756/e20230292.

References

Tarran R, Button B, Picher M, Paradiso A, Ribeiro C, Lazarowski E . Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections. J Biol Chem. 2005; 280(42):35751-9. PMC: 2924153. DOI: 10.1074/jbc.M505832200. View

Lazarowski E, Boucher R . Purinergic receptors in airway epithelia. Curr Opin Pharmacol. 2009; 9(3):262-7. PMC: 2692813. DOI: 10.1016/j.coph.2009.02.004. View

Okada S, Nicholas R, Kreda S, Lazarowski E, Boucher R . Physiological regulation of ATP release at the apical surface of human airway epithelia. J Biol Chem. 2006; 281(32):22992-3002. PMC: 2924190. DOI: 10.1074/jbc.M603019200. View

Ribeiro C, Paradiso A, Carew M, Shears S, Boucher R . Cystic fibrosis airway epithelial Ca2+ i signaling: the mechanism for the larger agonist-mediated Ca2+ i signals in human cystic fibrosis airway epithelia. J Biol Chem. 2005; 280(11):10202-9. DOI: 10.1074/jbc.M410617200. View

Paradiso A, Ribeiro C, Boucher R . Polarized signaling via purinoceptors in normal and cystic fibrosis airway epithelia. J Gen Physiol. 2001; 117(1):53-67. PMC: 2232471. DOI: 10.1085/jgp.117.1.53. View

Coote K, Paisley D, Czarnecki S, Tweed M, Watson H, Young A . NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia. Br J Pharmacol. 2015; 172(11):2814-26. PMC: 4439877. DOI: 10.1111/bph.13075. View

Devor D, Pilewski J . UTP inhibits Na+ absorption in wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. Am J Physiol. 1999; 276(4):C827-37. DOI: 10.1152/ajpcell.1999.276.4.C827. View

Cabrita I, Benedetto R, Schreiber R, Kunzelmann K . Niclosamide repurposed for the treatment of inflammatory airway disease. JCI Insight. 2019; 4(15). PMC: 6693830. DOI: 10.1172/jci.insight.128414. View

Tarran R, Button B, Boucher R . Regulation of normal and cystic fibrosis airway surface liquid volume by phasic shear stress. Annu Rev Physiol. 2006; 68:543-61. DOI: 10.1146/annurev.physiol.68.072304.112754. View

10.

Stoltz D, Meyerholz D, Welsh M . Origins of cystic fibrosis lung disease. N Engl J Med. 2015; 372(4):351-62. PMC: 4916857. DOI: 10.1056/NEJMra1300109. View

11.

Schroeder B, Cheng T, Jan Y, Jan L . Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008; 134(6):1019-29. PMC: 2651354. DOI: 10.1016/j.cell.2008.09.003. View

12.

Button B, Goodell H, Atieh E, Chen Y, Williams R, Shenoy S . Roles of mucus adhesion and cohesion in cough clearance. Proc Natl Acad Sci U S A. 2018; 115(49):12501-12506. PMC: 6298066. DOI: 10.1073/pnas.1811787115. View

13.

Scudieri P, Caci E, Bruno S, Ferrera L, Schiavon M, Sondo E . Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia. J Physiol. 2012; 590(23):6141-55. PMC: 3530122. DOI: 10.1113/jphysiol.2012.240838. View

14.

Yerxa B, Sabater J, Davis C, Stutts M, Lang-Furr M, Picher M . Pharmacology of INS37217 [P(1)-(uridine 5')-P(4)- (2'-deoxycytidine 5')tetraphosphate, tetrasodium salt], a next-generation P2Y(2) receptor agonist for the treatment of cystic fibrosis. J Pharmacol Exp Ther. 2002; 302(3):871-80. DOI: 10.1124/jpet.102.035485. View

15.

Boyle M, De Boeck K . A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med. 2014; 1(2):158-63. DOI: 10.1016/S2213-2600(12)70057-7. View

16.

Moss R . Pitfalls of drug development: lessons learned from trials of denufosol in cystic fibrosis. J Pediatr. 2013; 162(4):676-80. DOI: 10.1016/j.jpeds.2012.11.034. View

17.

Wheatley C, Baker S, Morgan M, Martinez M, Liu B, Rowe S . Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis. Respir Med. 2015; 109(8):1001-11. PMC: 4941831. DOI: 10.1016/j.rmed.2015.05.018. View

18.

Button B, Picher M, Boucher R . Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia. J Physiol. 2007; 580(Pt. 2):577-92. PMC: 2075559. DOI: 10.1113/jphysiol.2006.126086. View

19.

Henderson A, Ehre C, Button B, Abdullah L, Cai L, Leigh M . Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest. 2014; 124(7):3047-60. PMC: 4072023. DOI: 10.1172/JCI73469. View

20.

Namkung W, Phuan P, Verkman A . TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J Biol Chem. 2010; 286(3):2365-74. PMC: 3023530. DOI: 10.1074/jbc.M110.175109. View