Despite the discovery of the cystic fibrosis (CF) gene in 1989, there are no approved therapies that target the underlying defect in the CF gene product, the CF transmembrane conductance regulator (CFTR). Ninety percent of CF patients carry the F508del CFTR mutation that leads to defects in CFTR protein folding, preventing it from reaching the cell surface where it normally regulates salt transport and water movement across epithelial cells. Here, we describe the pharmacology of VX-809, an investigational small molecule CFTR corrector that increased the cell surface density of F508del-CFTR in vitro. In these studies, we show that VX- 809 increased the amount of properly folded CFTR that was able to exit from the endoplasmic reticulum and, as a result, increased anion transport across human CF airway cell cultures carrying the F508del-CFTR mutation on both alleles from 3% to approximately 15% of values observed in non-CF airway. This increase was sufficient to augment fluid secretion from these airway cultures, which could be further improved by the addition of VX-770, a CFTR potentiator. These in vitro studies suggest that small molecule drugs such as VX-809, either alone or in combination, may directly address the underlying genetic defect in CF to restore CFTR function.
Van Goor, F., Hadida, S., Grootenhuis, P. D. J., Stack, J. H., Burton, B., Olson, E. R., … Negulescu, P. (2010). Rescue of the protein folding defect in cystic fibrosis in vitro by the investigational small molecule, VX-809. Journal of Cystic Fibrosis, 9, S14. https://doi.org/10.1016/s1569-1993(10)60050-1