The widely used antifungal drug amphotericin B which is capable of forming ion channels in the cellular membrane of airway epithelial cells could hold therapeutic promise in treating patients with cystic fibrosis, according to a study published in Nature.
Cystic fibrosis is a chronic lung disorder caused due to a defect in a gene called CFTR (cystic fibrosis transmembrane conductance regulator). Mutation in this gene can result in abnormalities in the released ion-channel protein which can cause problems in the transport of chloride (Cl-) and bicarbonate (HCO3- ) ions in the epithelial cells that line the airways of lungs. This results in a build-up of mucous in these airways obstructing the normal process that removes mucus and the inhaled bacteria which gets trapped in it leading to persistent infections and inflammation, which destroy lung tissue.
Amphotericin B, which is synthesized naturally by bacteria, forms non-selective ion channels that are permeable to both anions and cations, and can take advantage of the systems that regulate ion flow through the cell.
The researchers tested amphotericin B in vitro human cells derived from CF patients and in pig models of the disease.
When added to the apical membrane of human airway cells in vitro HCO3- was secreted from the cells which increased the pH of the airway-surface liquid and restored its volume to normal levels when compared to the cells which did not receive the drug. Demonstration of the drug in the in vivo pig model of CF also helped restore ion channels and enhance antibacterial defences in the cell helping clear the airways of the lungs.
Amphotericin was also tested in airway epithelial cells obtained from patients whose CFTR represented a range of variant of the protein. Addition of drug to the apical surface of these cells also resulted in an increase in pH, decrease in viscosity of the airway surface liquid and enhancement of bacterial killing compared to untreated cells. This shows that amphotericin has the potential to work regardless of the kind of mutation, and even when the protein is missing.
“The really exciting news is that amphotericin is a medicine that’s already approved and available on the market,” said Martin D. Burke, MD, PhD, leader of the study and a professor of chemistry at the University of Illinois in Champaign, mentioning on the accessibility towards the drug, in a press statement.
“Instead of trying to correct the protein or do gene therapy – the latter of which is not yet effective in the lung – we use a small molecule surrogate that can perform the channel function of the missing or defective protein,” he added.