Pitfalls of drug development: Lessons learned from trials of denufosol in cystic fibrosis

摘要

The life-shortening genetic disease cystic nbrosis (CF) is caused by mutations in the CF gene on both alleles, resulting in failure of a defective CF transmembrane conductance regulator (CFTR) glycoprotein to normally regulate chloride and bicarbonate flux at the airway surface.1 According to a leading theory of CF pathogenesis, the "volume depletion" hypothesis, this abnormal anion transport leads to reduced airway surface liquid, airway dehydration, and impaired mucociliary clearance, resulting in vulnerability to airway obstruction, microbial infection, and inflammation.2 In 1991, investigators at the University of North Carolina discovered that triphosphate nucleotides, such as adenosine-5'-triphosphate and uridine-5'-triphosphate, stimulated chloride secretion in both normal and CF respiratory epithe-lia,3 offering a potential bypass mechanism for defective CFTR. Triphosphate nucleotides transduce a signal by binding to purinergic receptors on respiratory epithelial cells specifically responding to purine and pyrimidine nucleotides, termed P2Y2 receptors. This leads to release of intracellular calcium and activates calcium-dependent chloride channels (CaCCs) distinct from CFTR.4 In vitro tissue culture studies have confirmed that adenosine-5'-triphosphate and uridine-5'-triphosphate can restore liquid transport in CF cultures within a few minutes, enhance tracheal mucus velocity in sheep models, and acutely increase sputum volume and mucociliary clearance in smokers.5 Additional actions of P2Y2 agonists also have been reported from cell culture experiments, including stimulation of ciliary beat frequency, increased mucin secretion from goblet cells and surfactant from type II alveolar cells, and inhibition of epithelial sodium absorption,5'6 the net sum of these plausibly resulting in improved airway hydration and increased mucociliary transport that should be beneficial in treating CF.