Editors' ChoiceCystic Fibrosis

Enhancing Chloride Transport

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Science Translational Medicine  28 Oct 2009:
Vol. 1, Issue 4, pp. 4ec16
DOI: 10.1126/scitranslmed.3000517

Cystic fibrosis (CF) patients are plagued by thick mucus in their lungs and elsewhere, which leads to fibrous scars, infections, and loss of lung function. Caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, CF is the most common fatal genetic disorder among Caucasians. In recent years, improved therapies—including anti-inflammatory agents, mucus-thinners, and antibiotics—have increased life expectancy to ~40 years. All therapies currently in use, however, treat secondary symptoms, rather than loss of CFTR function. CFTR, a protein kinase A–activated ion channel, normally secretes chloride from epithelial cells and thereby allows water to follow by osmosis, increasing mucus fluidity. Some CFTR mutations (for example, F508del) affect CFTR delivery to the cell surface; others (G551D) impair channel opening. Directly increasing CFTR function in CF patients represents an alternative treatment possibility. Previously, Van Goor et al. identified a small molecule, VX-770, that increases regulated ion flow through CFTR and has shown promise in Phase 2 clinical trials. Now, these researchers describe its in vitro pharmacology. They found that it increases chloride secretion from F508del-CFTR and G551D-CFTR only after they are activated by protein kinase A, meaning that the normal physiological control over CFTR function remains. The compound acted by increasing the time CFTR stays in the open conformation. Furthermore, VX-770 increases chloride secretion from human CF bronchial epithelia carrying both G551D and F508del mutations to ~50% of the level seen in healthy epithelia. The compound increases the amount of fluid on the apical surface and enhances cilia beating (which does not occur normally in CF) in these cultures, supporting the idea that increasing CFTR function can restore CF epithelial cell function.

F. Van Goor et al., Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl. Acad. Sci. U.S.A. 21 October 2009 (10.1073_pnas.0904709106) [Full Text]

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