An approved drug normally used to treat fungal infections could also do the job of a protein channel that is missing in the lungs of people with cystic fibrosis, operating as a prosthesis on the molecular scale, according to the new research from the University of Illinois. Cystic fibrosis is a lifelong disease that makes patients vulnerable to lung infections. There are treatments for some but not all patients, and there is no cure. The drug restored infection-fighting properties in lung tissue donated by human patients as well as in pigs with cystic fibrosis. It has potential to become the first treatment to address all types of cystic fibrosis, regardless of the genetic mutation that causes the protein deficiency.
Instead of trying to do gene therapy, the researchers use a small molecule surrogate that can perform the channel function of the missing protein, which we call a molecular prosthetic. Healthy lungs have a layer of liquid on the surface of the airways that helps protect against infection. Cells in the lining of the lung secrete bicarbonate, or baking soda, into the liquid to make it inhospitable to invading bacteria. However, in people with cystic fibrosis, the protein in the cell membrane that vents the bicarbonate to the surface, called CFTR, is defective or missing altogether.
The team has long investigated the channel-forming properties of a drug used to treat fungal infections, amphotericin (am-foe-TARE-is-in). In the new study, the researchers explored it as a treatment candidate for cystic fibrosis. They found that amphotericin can form channels in the surface membrane of lung tissue donated by people with cystic fibrosis that was caused by various mutations in the CFTR gene. The channels released bicarbonate that had built up in cells and brought the pH and thickness of the airway surface liquid back within normal range.
The researchers also treated pigs with cystic fibrosis using a version of amphotericin formulated for delivery to the lungs. In both the experiments, in human tissue and in pigs, the researchers saw a restoration of the infection-fighting properties in the liquid lining the lung surfaces. Unlike drugs that target defective CFTR proteins and work to correct their misfolded structure, the molecular prosthetics approach bypasses the defective protein to form new channels - an important feature for the 10 percent of people with cystic fibrosis who are completely missing the CFTR protein and therefore cannot be treated with corrector drugs.
Whereas many of the latest advances in cystic fibrosis treatment have been targeted to specific mutations, this approach would benefit everyone with cystic fibrosis, regardless of mutation. Next, the research team will conduct clinical trials to see whether amphotericin delivered to the lungs is effective in humans with cystic fibrosis.