TMEM16A was recently identified as a calcium-activated chloride conductance and a key orchestrator of anion secretion in the human airway epithelium (Caputo et al 2008; Schroeder et al 2008; Yang et al 2008). It is now clinically established that promoting anion secretion in the airway leads to enhanced mucus clearance and reduced exacerbation frequency in CF patients and as such TMEM16A represents an important target for the next generation of mucokinetics. Importantly, positive regulators of TMEM16A function will be expected to be of benefit in all CF patients, irrespective of their CFTR mutational status.
A screen of microbial-derived products using a 3D model of the human airway epithelium (bronchospheres) revealed flagellin (FLG) as a potential regulator of mucociliary structure and function. Flagellin, a TLR5-agonist, is the key protein component of bacterial flagella expressed by a number of organisms including Pseudomonas aeruginosa. Considering that mucus plugs in the airways of many cystic fibrosis (CF) patients would be reasonably expected to contain FLG, the epithelium is likely to be chronically exposed to this bacterial protein.
Enterprise Therapeutics is a drug discovery company dedicated to the research and development of novel therapies for the treatment of respiratory diseases. The company is based in the UK with offices at the Sussex Innovation Centre.
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