Cystic fibrosis is possibly the most visible reminder of the failure—so far at least —to convert advances in understanding the molecular underpinnings of genetic disease into clinically useful therapies. The condition is caused by mutations in a gene encoding a chloride-selective ATP-binding cassette transporter called cystic fibrosis transmembrane conductance regulator (CFTR). Defects in this CFTR protein affect the transport of chloride and other ions across the cell membrane, leading to the accumulation of thick, sticky mucus in the lung, and giving rise to persistent lung infections. Other complications include malnutrition and poor weight gain due to pancreatic insufficiency, electrolyte imbalances and male infertility due to blockage of the vas deferens. Diabetes, osteoporosis and liver disease are also associated with the condition.
CFTR was cloned and sequenced more than 20 years ago (Science 245, 1066–1073, 1989), but efforts arising out of this work, involving both drug- and gene-therapy–based approaches, failed to make much headway. Drug discovery attempts, based on a variety of CFTR channel modulators or 'potentiators', including flavonoids, sulfonamides, phenylglycines and benzimidazolones, foundered due to poor potency or excessive toxicity (Pharmacol. Ther. 125, 219–229, 2010). Experimental gene therapies have been stymied repeatedly by a lack of suitable vectors and poor efficacy.
This is a preview of subscription content, access via your institution