More than two decades after scientists discovered the mutated gene responsible for cystic fibrosis, the first drugs that target the defective protein involved in the disease may be on the cusp of market approval. In February, researchers announced preliminary results from a phase 3 trial showing that a pill called VX-770 led to substantial improvements in lung capacity in people with cystic fibrosis. Similar drugs in development could also reach patients within the next few years.
“This is one of the most exciting developments in [cystic fibrosis] therapies since I’ve been practicing,” says Paula Anderson, a pulmonary physician at the University of Arkansas for Medical Sciences in Little Rock. “We’ve never had any other treatment that was really specifically targeted at mutations.”
In 1989, a team that included Francis Collins, now director of the US National Institutes of Health, showed that mutations in a gene encoding a chloride channel protein called cystic fibrosis transmembrane conductance regulator, or CFTR, are always responsible for cystic fibrosis, an inherited disorder that slows mucus clearing from the airways and thereby makes individuals susceptible to deadly lung infections1, 2, 3. After the landmark genetic discovery, researchers widely assumed that cures would be just around the corner. But no approved therapies to date target the underlying genetic defect; instead, existing therapies such as antibiotics and mucus-thinning drugs can only treat the symptoms of the disease.
VX-770 is different. This small-molecule drug from Vertex Pharmaceuticals, a Cambridge, Massachusetts–based company, interacts directly with CFTR, propping open the defective protein to allow a more normal flow of chloride ions across the cell membrane, thereby restoring the function of airway cells. In the recently announced trial, which enrolled 161 participants who carried at least one copy of a CFTR mutation called G551D, the people taking VX-770 showed improved lung function and reported fewer respiratory problems than those on placebo. The drug also restored chloride levels in patients’ sweat to near-normal levels, indicating that the chloride pumps throughout the body were back up and running.
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Image: CFTR, Creative Commons