TMEM16A (ANO1) as a therapeutic target in cystic fibrosis

Cystic fibrosis (CF) is a multi-organ genetic disease caused by loss of function of CFTR, a cAMP-regulated chloride channel expressed in epithelial cells. In airway epithelia, CFTR-dependent chloride secretion is required to humidify mucosal surface and to allow efficient mucociliary clearance. In CF patients, CFTR deficit causes chronic bacterial infections and airway obstruction by mucus accumulation. Airway epithelial cells also express TMEM16A (ANO1), a second type of chloride channel, whose activity is controlled by cytosolic calcium concentration. Pharmacological stimulation of TMEM16A could be beneficial to bypass CFTR defect. However, the relationship of TMEM16A with mucus hypersecretion needs to be clarified. Multiple large scale screenings have been carried out to identify inhibitors and activators/potentiators of TMEM16A, including CaCC_inh-A01, T16_inh-A01, Ani9, TM_inh-23, MONNA, E_act, and ETX001. Such compounds are important as research tools, to assess the role of TMEM16A in health and disease, and as possible therapeutic agents.