A research team from Stanford Medicine has made a surprising discovery that could have a positive impact on patients with cystic fibrosis (CF). In a study performed on animal models, two types of existing medications given together improved the clearance of mucus in the lungs.
The findings are detailed in the paper, “Therapeutic Potential of Synergistic Mucociliary Clearance for Cystic Fibrosis Airways by β-Adrenergic Plus Cholinergic Agonists,” published in the Journal of Clinical Investigation.
“I really hope this discovery can help CF patients,” said lead author Nam Soo Joo, PhD, a senior research scientist at Stanford Medicine, in a news release. “If these drugs improve mucociliary clearance in people as much as they do in our animal models, we expect this to help remove pathogens from the lungs and reduce patients’ airway infections.”
The two drugs — formoterol (a beta adrenergic agonist) and methacholine (a low-dose cholinergic agonist) — are already approved by the U.S. Food and Drug Administration (FDA) for other uses. The researchers tested the combination therapy in a small group of individuals, with and without CF, and determined it was safe and well-tolerated.
The researchers’ findings were made unintentionally while evaluating multiple drugs’ abilities to speed up mucociliary clearance, Dr. Joo said. They initially applied the formoterol-methacholine therapy to lung tissue in a petri dish to check its viability for use as an experimental control. What they found was it actually sped up mucociliary clearance — the objective of the study.
Dr. Joo said the team was especially surprised by this result because, when used separately, the two drugs do not help individuals with CF. Beta adrenergic agonists trigger an abnormal response, and cholinergic agonists cause asthma-like airway constriction, he said.
The researchers initiated a second study to analyze the dual therapy in animal lung tissue samples and observed positive results. In rats with CF, the treatment increased mucociliary clearance velocity to approximately 80% of that seen in healthy rats.
Additional key findings included:
- Testing on animal tracheal tissue showed increased fluid secretion, suppressed fluid absorption and high secreted fluid pH — all of which make mucus thinner and more mobile.
- Testing on ferrets with CF showed improved results when dual therapy was administered with a cystic fibrosis transmembrane conductance regulator (CFTR) modulator compared to a CFTR modulator alone.
The novel approach could be a beneficial option for the estimated 20% of patients with CF who do not respond to CFTR modulators, Dr. Joo said. The therapy may also help patients with other respiratory conditions, such as COPD or bronchiectasis, he said.
“If we use this drug in other airway diseases, it may improve those patients as well, but we still require large-scale clinical trials to know the optimal combination and concentrations of these drugs,” Dr. Joo said.
The research team, led by Carlos Milla, MD, said it is planning a clinical trial to test the combination therapy’s efficacy in CF patients. Dr. Milla is a professor of pediatrics at Stanford Medicine and a pulmonologist who works with CF patients at Stanford Medicine Children’s Health.
