Researchers Find Drug May Help Cystic Fibrosis Patients

People with cystic fibrosis have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which normally codes for a protein that transports chloride across the cell membrane.

Approximately 70% of cystic fibrosis patients have the same mutation (called the deltaF508 mutation) in this gene, which results in a protein that is partly functional but that rarely gets transported to the surface of the cell. Instead, this protein become “stuck” on the way to the surface and is degraded. Consequently, little or no chloride can be transported across the cell membrane. In cystic fibrosis, this chloride imbalance results in a thick mucus that causes recurrent airway and intestinal obstructions, as well as chronic respiratory infections.

The addition of sodium 4-phenylbutyrate (4PBA) to cells with the deltaF508 mutation allows more CFTR proteins to reach cell surfaces, where they can transport chloride, according to Ronald C. Rubenstein, M.D., Ph.D., an instructor in pediatrics at Hopkins and lead author of the study. This phenomenon occurs at concentrations of 4PBA normally seen in patients who already take the drug for urea cycle disorders, which are genetic diseases characterized by high levels of ammonia in the bloodstream.

The study appears in the November 15 issue of the Journal of Clinical Investigation.

“A therapy directed at correcting the abnormal intracellular transport of the deltaF508 mutation is potentially beneficial to the majority of CF patients,” says Rubenstein. “We are very encouraged by 4PBA’s apparent action to repair this mutation’s function in the lab.”

Cystic fibrosis occurs in about one in every 2,500 births in the Caucasian population, one in every 16,000 births in the African American population, and about one in every 90,000 births in the Asian American population.

“There are currently an estimated 23,000 patients diagnosed with CF in the United States, with an average survival age of 31 years,” says Pamela Zeitlin, M.D., Ph.D., associate professor of pediatrics at Johns Hopkins and a co-author of the study. “4PBA has the potential to benefit more than two-thirds of these patients.”

However, say Rubenstein and Zeitlin, it is not clear if this therapy alone would lead to significant improvement in patients. Even if the mutant proteins reach cell surfaces, they still cannot transport as much chloride as normal proteins do.

Rubenstein and Zeitlin are currently conducting clinical trials of 4PBA in CF patients who have the deltaF508 mutation.

Marie E. Egan, M.D., of Yale University, is also an author of the study.

The Johns Hopkins Children’s Center is the children’s hospital of the Johns Hopkins medical institutions. Maryland’s most comprehensive acute-care hospital for children, the center, with its 177-bed hospital and more than 40 divisions and services, treats some 8,000 inpatients and more than 64,000 outpatients annually.