Editors' ChoiceCystic Fibrosis

Targeting the Channel: CF Treatment Gets Personal

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Science Translational Medicine  22 Dec 2010:
Vol. 2, Issue 63, pp. 63ec197
DOI: 10.1126/scitranslmed.3002058

It has been more than 20 years since scientists pinpointed the gene that is mutated in the inherited disease cystic fibrosis (CF). But treatments for CF remain mostly supportive, addressing the disease’s symptoms—infections, lung congestion, and malnutrition—rather than its cause. The genetic culprit is a mutated CFTR gene, which encodes the CF transmembrane conductance regulator, an ion channel in the epithelium of multiple organs that is responsible for salt and fluid transport. Disruption of CFTR function in the epithelium leads to the myriad symptoms associated with CF, most notably the buildup of sticky mucous in the lung and digestive system. Although current treatment strategies have substantially reduced disease morbidity, new approaches are needed to increase the average life expectancy of CF patients, which is estimated to be ~37 years. Getting to the root cause of the disease—CFTR dysfunction—is one approach that has the potential to improve epithelial function in all organs. Now, Accurso et al. report the successful treatment of some CF patients with a drug that targets a specific mutated form of CFTR.

The disease-causing mutations in CFTR give rise to aberrations that lead to scenarios in which the CFTR protein either is not synthesized, is not processed properly and thus cannot reach the epithelial membrane, or is synthesized, processed, and reaches the cell membrane but is nonfunctional. The third situation, in which CFTR reaches the epithelial cell surface but is not active, is caused by a mutation that alters amino acid 551 (G551D, a glycine–to–aspartic acid change). Drugs that enhance function of the mutated CFTR protein at the epithelial cell surface are known as potentiators and have shown a great promise in in vitro studies in CF cells. In a recent clinical trial designed to assess a new potentiator agent, VX-770, Accurso et al. showed that the drug boosts the activity of CFTR in CF patients who carry the G551D mutation.

The authors used a randomized, placebo-controlled clinical trial to evaluate the safety and adverse effects of VX-770 as primary endpoints and improvements in CFTR function and pulmonary status as secondary end points. They recruited 39 CF subjects who carried the G551D mutation on at least one allele from various CF treatment centers throughout the United States and randomly assigned them to groups that received either VX-770 or a placebo. In addition to having very few side effects, VX-770 improved CFTR ion-channel function in both the nasal epithelium and sweat glands, as well as lung function in drug-treated subjects relative to controls. The drug-related decrease in sweat chloride content was dramatic, a feature not seen with any other compound tested thus far. These early efficacy findings with VX-770 as well as its safety profile support further clinical evaluation of this drug in select CF patients with G551D mutations.

F. J. Accurso et al., Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N. Engl. J. Med. 363, 1991–2003 (2010). [Abstract]

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