Cystic fibrosis (CF) is a genetic disorder that causes multiorgan morbidity and premature death, most commonly from pulmonary dysfunction. Mutations in the CF transmembrane conductance regulator (CFTR) gene, of which almost 2000 have been described, result in a dysfunctional CFTR protein. This protein is an adenosine triphosphate binding anion channel, present primarily at the surface of epithelial cells. Loss of function mutations in this anion channel result in decreased or absent chloride/bicarbonate transport. The subsequent abnormal salt and water transport at epithelial cell surfaces leads to thickened secretions, and infection or inflammation in affected organs. In the last 20 years, therapeutics have been developed to treat the signs and symptoms of CF. However, in 2012, the small molecule drug, ivacaftor, became the first approved therapy that addresses the basic defect in CF. Ivacaftor is a potentiator of CFTR channels defective in their chloride/bicarbonate gating/conductance, but present at the epithelial cell surface. It is only approved for 10 mutations carried by approximately 7% of the population of patients with CF. F508del is the most common CFTR mutation, present in homozygosity in approximately 50% of patients with CF. The F508del mutation results in multiple CFTR channel defects that require both correction (stabilization of misfolded CFTR and trafficking to the epithelial cell membrane) and potentiation. This article reviews the in vitro and clinical trial data for the potential use of the potentiator, ivacaftor, and the corrector, lumacaftor, in patients with CF.
Keywords: corrector; cystic fibrosis; cystic fibrosis transmembrane conductance regulator modulator; ivacaftor; lumacaftor; potentiator.
© The Author(s), 2015.