An antifungal small molecule drug could restore some of the function lost in cystic fibrosis.
Cystic fibrosis is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ion channel that transports chloride, bicarbonate, and other anions across the membranes of epithelial cells lining lung airways. When the CFTR ion channel doesn’t work, it adversely affects the pH and viscosity of the liquid lining the airway surface and reduces an individual’s defenses against microorganisms.
Martin D. Burke of the University of Illinois at Urbana–Champaign and coworkers added the drug, amphotericin B, to cultured epithelial cells from people with cystic fibrosis. They used both immortalized cell lines and cells obtained directly from people with different CFTR mutations. The drug inserted into cell membranes, formed simple ion-channel-like structures, and increased the flow of bicarbonate ions out of epithelial cells. In tests in which the cells formed structures like those lining airways, treatment with the molecule increased the pH and decreased the viscosity of the liquid secreted on the structure’s surface, improving the liquid’s defenses against microorganisms (Nature 2019, DOI: 10.1038/s41586-019-1018-5).
Burke’s lab teamed up with Michael J. Welsh, a leading cystic fibrosis researcher at the University of Iowa, who has engineered pigs lacking the CFTR protein. When the researchers administered amphotericin B inside liposomes directly to the trachea of these pigs, the pH of the airway surface liquid increased.
Because amphotericin B’s effects are independent of CFTR, Burke hopes that the drug could work for all people with cystic fibrosis, regardless of whether they have a malfunctioning CFTR or one that’s completely missing.
“This paper convinced me that amphotericin B should be considered for further testing for treating CF lung disease,” says Terry E. Machen, an emeritus professor at the University of California, Berkeley, who studies ion transport in cystic fibrosis. “A number of other artificial anion channels have been tested previously, but none with the depth and vigor as the present publication. In addition to stimulating further research on amphotericin B alone, perhaps this paper will also prompt further investigations of other artificial channels/transporters that could be similarly helpful for treating CF lung disease.”
“Whether this can effectively treat CF lung disease remains a question,” says Steven M. Rowe, director of the Cystic Fibrosis Research Center at the University of Alabama at Birmingham. “There is quite a bit to do before we alter care of CF patients.” It needs to be tested in animal models of CF lung disease, rather than just in tests of cell physiology, he says.
Getting to this point has been a 14-year journey for Burke. He remembers being an MD/PhD student explaining in detail the problems associated with CFTR to a young woman with cystic fibrosis. “At some point in the conversation, she stopped me and said, ‘It sounds like you know exactly what’s wrong. Why can’t you fix it?’” Burke says. “That was a life-changing conversation for me.”
Burke’s dream is to be able to treat cystic fibrosis with an inhaler, much like how asthma is treated. He hopes that amphotericin B could be that inhaled drug.
“The next step is clinical trials,” Burke says. A number of studies of amphotericin B as an antifungal agent have already shown that the drug can be safely administered to the lung. “We think there’s a chance to move forward quickly and safely to get an answer to the really important question: Can this work for people with CF?” he says.