With fewer than 80,000 people in the world diagnosed with cystic fibrosis, the disease hardly presents itself as a lucrative market for drug development. But it's not just people with cystic fibrosis who harbor mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. “There are other diseases that CFTR mutations are associated with,” notes Melissa Ashlock, former vice president of drug discovery for Cystic Fibrosis Foundation Therapeutics. As such, CFTR modulators designed for one ailment—be it cystic fibrosis or otherwise—could have broader market potential beyond the single orphan disease.

Although most people with mutations in CFTR develop cystic fibrosis, some individuals experience less severe disorders, including chronic pancreatitis, male infertility, sinusitis and airway abnormalities. These people are also likely to benefit from CFTR-targeted agents such as Vertex Pharmaceutical's VX-770 and VX-809. But, given that many of these more mild diseases are more sporadic than cystic fibrosis, “whether they would be good candidates for being treated with a chronic therapy that's going to be quite expensive is unclear,” says Sam Moskowitz, director of the cystic fibrosis basic science program at MassGeneral Hospital for Children in Boston.

Likewise, PTC Therapeutics's lead cystic fibrosis compound ataluren also might find a broader audience beyond cystic fibrosis by helping ribosomes read through premature stop codons associated with other genetic disorders. Currently, ataluren is being tested in people with forms of hemophilia and a metabolic disorder called methylmalonic acidemia, but the drug could also prove beneficial to people with certain forms of muscular dystrophy, lysosomal storage disorders and some types of cancer. “That definitely has potential generalizability,” Moskowitz says.

Taking a different tack, some drug companies are also trying to block rather than enhance the function of CFTR to treat a range of diseases associated with the loss of bodily fluids. For example, two years ago the Swiss pharma giant Novartis teamed up with the Institute for OneWorld Health, a San Francisco–based nonprofit, to discover and develop new CFTR inhibitors to combat chronic secretory diarrhea. Similarly, San Francisco–based Napo Pharmaceuticals is advancing CFTR blockers that have proven effective in treating rodent models of cholera-induced diarrhea and polycystic kidney disease.

But it could be VX-770—a drug possibly on the brink of regulatory approval—that first proves to have wide-reaching utility. In work presented at last year's Annual North American Cystic Fibrosis Conference in Baltimore, Steven Rowe of the University of Alabama at Birmingham showed that the drug improved CFTR activity and mucus clearance in human lung cells exposed to cigarette smoke extract. The potential of this drug application was reinforced last month when molecular biologist Neeraj Vij of Johns Hopkins University School of Medicine in Baltimore reported that CFTR is involved in regulating cell death and degradation responses in mice with smoke-induced lung damage (Am. J. Physiol. Lung Cell. Mol. Physiol. doi:10.1152/ajplung.00408.2010, 2011).

Given that chronic obstructive pulmonary disease is the fourth leading cause of death in the US and Europe and no pharmacological treatments are available that address the mucus buildup associated with this disease, “agents that potentiate CFTR activity could be a useful addition to the treatment armamentarium if the approach can be successfully translated to humans,” Rowe says.