New Cystic Fibrosis Drug Counteracts Benefits of Another

A new cystic fibrosis (CF) drug appears to counteract the molecular effects of another drug for the condition, according to a recent study from researchers at the University of North Carolina (UNC) School of Medicine and the Marisco Lung Institute.

Published in Science Translational Medicine, the study found a mutant CFTR protein becomes unstable and loses some of its functionality when the patient takes the 2 CF drugs.

“In our human airway epithelial model system, one of the drugs destabilizes and deactivates the protein that the other drug tries to correct,” Martina Gentzsch, PhD, an assistant professor at UNC and senior author of the paper, said in a statement from the school. “Our data suggest that drug developers should take this destabilization effect into account in order to alleviate CF symptoms to a greater degree.”

Patients with CF have 2 faulty copies of the CFTR with some not having enough proteins that move to the cell surface while others no not function properly, according to UNC. The result of either malfunction results in poor mucus clearance from a patient’s lungs, lung infections, inflammation, and difficulty breathing, among other possible issues.

In an effort to treat the condition, scientists developed compounds called “correctors” to help move the right amount of proteins to the surface to help maintain an airway. They also created “potentiators” to “activate the CFTR channels at the cell surface to maintain the proper balance of electrolytes of fluids, including those found inside lungs.”

UNC noted that between 3% and 5% of CF patients have a genetic mutation that allows the epithelial cells to move enough CFTR proteins to the surface. The chloride channels in those patients also have defective activation. However, a potentiator called VX-770 (ivacaftor) has proved to work for patients with this mutation.

Other CF patients, the study noted, have the “transit” mutation, which does not allow them to bring the CFTR to the cell surface and requires a corrector and potentiator. Using tissue samples from CF patients with the “transit” genetic mutation (ΔF508), UNC postdoctoral fellow Deborah Cholon studied the samples and their interaction with the drugs.

The study grew cultured CF epithelial cells in a way similar to a human lung. The researchers also treated the cells with a corrector called VX-809 (lumacaftor) for 2 days. The team reported observing an improvement in CFTR protein moving to the cell surface. Shortly after, they added the potentiator VX-770 and observed a brief increase in function that “rapidly waned.” As a result, they reported it as a “sign that the corrected CFTR protein was losing its ability to function as an ion channel.”

Also part of the study, the team treated the CF cells for 2 days with a potentiator and corrector simultaneously to see the result. Gentzsch reported the potentiator compound “chronically destabilized the CFTR protein, and that the destabilization was dependent upon the dose of VX-770.”

“The result was striking,” she noted. “The potentiator acted like an inhibitor of the corrector compound. We could see the corrected CFTR protein disappearing.”

Research for the study was funded by the National Institutes of Health, the Cystic Fibrosis Foundation, and the Else Kroner-Fresenius Stifung.