TMEM16A Potentiation: Possible Drawbacks

To the Editor:

Dr. Danahay and colleagues present an interesting and timely study of TMEM16A potentiation to increase the epithelial fluid secretion and thereby enhance mucus clearance in cystic fibrosis (CF) (1). They report that the novel compound ETX001 potentiates the opening of TMEM16A channels and augments the magnitude of the chloride current. In human cell and animal models, the ETX001 effect was independent of CFTR function. The authors conclude that the novel potentiator could also be suitable for patients with CF without mutation in CFTR. However, when previous investigations of TMEM16A are considered, this approach may raise concerns with respect to safety.

TMEM16A, a protein encoded by the gene ANO1, is a calcium-activated chloride channel robustly expressed not only in epithelial cells but also in smooth muscle cells of airways, pulmonary and systemic vessels, gastrointestinal smooth muscle cells, and the endothelial cells of pulmonary arteries (2). The wide distribution of the channel indicates diversity in its physiological functions, such as secreting chloride and regulating vascular and gastrointestinal tone. In addition, in the pacemaker cells of the gut, TMEM16A is important for peristalsis generation. Under physiological conditions, TMEM16A is active at the resting membrane potential, and the open probability is dependent on the intracellular calcium concentration. The chloride current is voltage-dependent and exhibits a greater current amplitude in a depolarized state than at hyperpolarization.

In addition to its physiological function, TMEM16A can be upregulated by, for example, ET-1 (endothelin-1), the transcription factor HIF-1α, or IL, factors that have been found to be important players in the pathology of pulmonary arterial hypertension (PAH). We have recently reported that TMEM16A is strongly upregulated in remodeled pulmonary arteries from patients with idiopathic PAH and that this change causes the depolarization of pulmonary arterial smooth muscle cells as well as a contraction of small pulmonary arteries (3). These detrimental changes were reversed by TMEM16A silencing or its pharmacological inhibition. We have shown that such inhibition reduced the increased pulmonary vascular tone in both ex vivo and in vivo settings and reversed pulmonary arterial remodeling, causing amelioration of pulmonary hypertension and right ventricular strain in two independent PAH animal models (3). TMEM16A overactivation was observed in inflammatory lung diseases, in which it was strongly upregulated in secretory cells and airway smooth muscle cells, significantly contributing to asthmatic hyperresponsiveness (4). Accordingly, inhibition of TMEM16A is considered a potential therapeutic target for asthma, other chronic obstructive lung diseases, and PAH.

Dr. Danahay and colleagues have mentioned their unpublished observations about the lack of any bronchospasm during the inhalation of the nebulized ETX001 in a conscious sheep model. However, inhaled drugs such as nitric oxide have strong pulmonary vasoactive effects when they come into close contact with the precapillary vessels. Some inhaled drugs such as iloprost may also be taken up into the systemic circulation where they come into contact with all the organs (5). Therefore, inhaled medications are not completely restricted to the airways.

In addition, in patients independent of CFTR genotype, activation of TMEM16A by denufosol failed to demonstrate any benefit to patients with CF. In a multicenter, randomized, parallel group, double-blind, placebo-controlled trial, the aerosol induced a cough or coughing in more than half of the patients. This adverse effect could be associated with additional mucus production but also with airway obstruction (6).

The proposed activation of TMEM16A as a druggable target in patients with CF poses a number of difficult questions. Enhancement of TMEM16A activity represents an option to improve chloride channel function in CF; however, it also bears risks for clinical complications such as bronchial obstruction, pulmonary hypertension, and disturbances in gut motility. Therefore, any prospective clinical trial should pay special attention to such potential adverse effects.