Molecular repair of a defective CFTR protein in cystic fibrosis

We analyse a paper, which reports an entirely novel approach to the treatment of cystic fibrosis, consisting in "repairing" the defective mutant protein. Patients with cystic fibrosis have a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride channel involved in salt and fluid transport in multiple organs, including the lungs and pancreas. The mutations have different effects on the CFTR protein, such as misfolding for the ΔF508 mutation (the most common), or defective opening of the chloride channel for the G551D-CFTR mutation, found in 4 to 5% of the patients. The authors of this work have shown that VX-770, an agent known previously to increase the activity of wild-type and G551D-CFTR cell surface protein in vitro, was able, when given orally to 39 cystic fibrosis patients during 14 and 28 days, to partially restore chloride conductance, as measured by nasal epithelium potential difference. Similarly, the agent partially restored chloride transport in sweat glands, as measured by the sweat chloride concentration. Clinically, VX-770 increased the forced expiratory volume per second (FEVi). Side effects included macular skin rash, elevation of blood glucose concentration and glycosuria. All side effects resolved after discontinuation of the drug. VX-770 has also been shown to increase the activity of ΔF508-CFTR channels in vitro, provided they reach the cell surface. This study appears to be a milestone in the treatment of cystic fibrosis and possibly other genetic diseases.