Amphotericin Holds Promise as Treatment for All CF Patients, Preliminary Study Shows

Amphotericin B, a widely used antifungal medication, may be a potential treatment to restore lung mucus properties, including its ability to fight infections, in people with cystic fibrosis (CF), a preliminary study shows.

The medicine creates pores in the membrane of cells lining the airways, working as a substitute channel for CFTR, which is the protein missing or defective in people with CF. This deficiency can be caused by several different types of genetic mutations in the CFTR gene.

Looking at human lung tissue and pig models of CF, researchers demonstrated that amphotericin restored the flow of bicarbonate ions out of lung cells, bringing the pH levels, viscosity, and antibacterial activity of the airway surface liquid back to normal.

Researchers say the therapy may hold promise as the first treatment suitable for all types of CF, regardless of the underlying CFTR mutation.

The study, “Small-molecule ion channels increase host defenses in cystic fibrosis airway epithelia,” was published in the journal Nature.

The CFTR protein channel is essential for regulating the release of salts, such as chloride and bicarbonate ions, out of cells, a process important for the production of sweat, saliva, and airway mucus.

A mucus with the correct viscosity and pH is needed for the lungs to work properly, and keep infections away. Bicarbonate, for instance, is a key antimicrobial agent.

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Losing the CFTR channel makes airway surface mucus more acidic and disrupts salt secretion.

“These defects cripple two important lung defenses: the antibiotic activity of airway liquid and the clearance of mucus. As a result, people become vulnerable to infection,” Michael J. Welsh, MD, a professor at the University of Iowa Carver College of Medicine, and co-author of the study, said in a University of Illinois news story written by Liz Touchstone.

Welsh is also a researcher at Howard Hughes Medical Institute. His group, together with the lab of professor Martin D. Burke, PhD, MD, at the University of Illinois, explored an alternative treatment to rescue cells from the CFTR defect.

“Instead of trying [to] do gene therapy — which is not yet effective in the lung — or to correct the protein, our approach is different. We use a small molecule surrogate that can perform the channel function of the missing protein, which we call a molecular prosthetic,” Burke said.

Using cells that line the lungs — airway epithelial cells — donated by CF patients with various CFTR mutations, the researchers found that amphotericin B can form channels at the surface of those cells, releasing the bicarbonate stuck inside them. The treatment also helped normalize pH levels and the thickness of the airway mucus.

The team also treated a pig model of CF, which lacked the CFTR gene, with an amphotericin formulation designed to target the lungs. In both human tissue and in pigs, the treatment was able to restore the antibacterial-fighting properties of the liquid lining airway surfaces.

“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,” Burke said.

The ability of amphotericin to bypass the CFTR defect and create new channels means it may be able to treat CF patients who completely lack CFTR, for whom no treatment exists yet.

“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,” said Emily Kramer-Golinkoff, co-founder of CF foundation Emily’s Entourage, which partly funded the research.

“Second, and perhaps even more importantly, this approach presents an opportunity to repurpose an existing, approved drug and bring it to the clinic quickly,” she added.

Next, the Illinois-Iowa research team are hoping to start clinical trials to test if amphotericin delivered to the lungs is effective for treating CF, “especially with people for whom correctors are not beneficial,” Burke said.

Because amphotericin is already approved, the path to the clinic is more direct, according to Burke. “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,” he said.

A video of Burke explaining the findings is available here.