By David Douglas
NEW YORK (Reuters Health) - 22/3/2019
Amphotericin B treatment may be able to restore the infection-fighting properties of the lungs in cystic fibrosis by standing in for a missing or deficient protein channel, studies in pigs and in human lung tissue suggest.
Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) impair respiratory host defenses in people with cystic fibrosis, Dr. Martin D. Burke of the University of Illinois at Urbana-Champaign and colleagues explain in Nature, online March 13.
Amphotericin B is a small molecule that forms unselective ion channels. "Just as a simple prosthetic device can restore a lot of function to those missing a limb, we found that although amphotericin is not a perfect mimic of the CFTR protein, it can function as a bicarbonate channel and restore defense mechanisms in the airway surface liquid," Dr. Burke said in a statement.
In particular, in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, the team found that amphotericin restored airway surface liquid pH, viscosity and antibacterial activity.
In addition, in a pig model of cystic fibrosis using CFTR-null pigs, the team found that administration of liposomal formulation of amphotericin and cholesterol increased airway surface liquid pH.
Although amphotericin is prescribed as an antifungal, the researchers note that "it is markedly toxic in humans." They used very low concentrations or other methods to avoid damaging effects.
As Dr. Burke stated, "Since amphotericin is an already approved drug, the path to clinical translation is more direct. It's already been shown to be safe when delivered directly to the lung, and it doesn't get into the rest of the body, so we can avoid the negative side effects that the drug is known for."
In emailed comments to Reuters Health, Dr. Burke said, "Further studies still need to be done to determine whether this approach can be impactful in the clinic, but we are hopeful that this molecular prosthetics approach could potentially benefit all people with cystic fibrosis, including those that have mutations in CFTR that cause no protein to be produced and thus cannot respond to the currently available class of drugs that act as CFTR correctors."
Co-author of an accompanying editorial Dr. David N. Sheppard of the University of Bristol, in the U.K., told Reuters Health by email, "The authors' key observations are that amphotericin B, a small molecule that forms pores in cell membranes, restored ion transport and antibacterial defences to cystic fibrosis cells. This result might lead to new therapies for all people with cystic fibrosis."