Study identifies potential treatment for cystic fibrosis
BY KRISTA CONGER
A compound that has shown promise in combating some chronic inflammatory diseases may be useful in preserving lung function in cystic fibrosis patients, say researchers at the School of Medicine and Lucile Packard Children's Hospital. The researchers recently completed a Phase 1 clinical trial of the compound and have begun a Phase 2 trial to test its efficacy in more patients.
"These people basically destroy their lungs through ongoing inflammation and infection," said the study's first author Rabindra Tirouvanziam, PhD, a research associate in genetics. "We're optimistic that, with further research, we may be able to inhibit this process." The findings were published online March 13 in the Proceedings of the National Academy of Sciences.
Cystic fibrosis is the most common disease caused by a recessive gene in Caucasians; about one in 2,500 infants are affected. Although it was once fatal in childhood, the expected lifespan of sufferers has been increasing with new treatments. But the attendant lung inflammation and scarring still results in the loss of three to four percent of lung function every year.
"If we can make any headway into relieving or cutting back on the amount of inflammation on a day-to-day basis, we could impact their health in a big way," said Carol Conrad, MD, a pulmonologist at Packard Children's. Ibuprofen can slow the decline, but long-term use at high doses can negatively affect other organs.
The researchers gave 18 cystic fibrosis patients, including seven children, high oral doses of a compound called N-acetylcysteine for four weeks. NAC is used by the body to make glutathione, the body's main naturally occurring anti-oxidant. It has been tested with some success in people with chronic bronchitis, chronic obstructive pulmonary disease and other inflammatory lung problems.
People with cystic fibrosis have a defective or missing version of a protein responsible for releasing glutathione into the extracellular spaces. This problem is particularly acute in the airways, where bacteria accumulate. White blood cells known as neutrophils are called to the lungs to fight infection but stumble into an ambush. Although it isn't clear why, the arriving neutrophils are doomed. They act strangely and begin to die.
Before they expire, they secrete a factor called interleukin-8, which recruits yet more neutrophils to the scene. They also pepper the surrounding cells with high levels of oxidants and other tissue-damaging molecules and, in a final blow, release DNA and a protein called elastase, both of which increase the sticky, disease-trapping properties of the airway mucous. It's a vicious, viscous circle that leaves sufferers gasping for breath and prone to infection.
NAC treatment throws a wrench into this process. The researchers found that circulating neutrophils from cystic fibrosis patients contained much less glutathione than did neutrophils from healthy patients. They theorized that neutrophils must depend on cells around them to maintain their glutathione levels. In cystic fibrosis patients, that help isn't forthcoming, so the neutrophils don't function properly.
The NAC treatment not only increased the amount of glutathione in circulating neutrophils, it also decreased the number of neutrophils and the levels of elastase and interleukin-8 in the airways. It was safe and well tolerated by the participants, who said they felt better during the study. A Phase 2 trial to confirm the findings has already enrolled all its subjects.
Conrad and Tirouvanziam caution cystic fibrosis patients against self-medicating with NAC, which is available as a food supplement. Many of those formulations have little or no active compound; some contain a form of NAC that can be harmful to cystic fibrosis patients. The NAC in this study is specially formulated for medical use by a Canadian company and is not licensed for U.S. sales.
Other Stanford researchers involved in the study are Leonore and Leonard Herzenberg and Richard Moss. The Stanford researchers are listed as inventors on a provisional patent application covering NAC as a therapeutic agent for cystic fibrosis. Leonore and Leonard Herzenberg have a small equity stake in BioAdvantex, the NAC suppliers for the study.