Potential New Treatment for Cystic Fibrosis

Armen Hareyan's picture

Cystic Fibrosis

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 Stanford University School of Medicine and Lucile Packard Children's Hospital. The researchers have recently completed a Phase 1 clinical trial of the compound and have begun a Phase 2 clinical trial to test its efficacy in a larger number of patients.

"These people basically destroy their lungs through ongoing inflammation and infection," said research associate Rabindra Tirouvanziam, PhD, the first author of the study. "We're optimistic that, with further research, we may be able to inhibit this process." The findings were published in the early online edition of the Proceedings of the National Academy of Sciences on March 13.

Cystic fibrosis is the most common disease caused by a recessive gene in Caucasians; about one in 2,500 infants are affected. Although the disorder was formerly fatal in childhood, the expected lifespan of sufferers has been increasing steadily with the advent of 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 pediatric pulmonologist at Packard Children's and an assistant professor of pediatrics at Stanford medical school. Ibuprofen can slow the decline, but long-term use at high doses can negatively affect the kidney and gastrointestinal tract as well as other organs.

The researchers gave 18 cystic fibrosis patients, including seven children ten years or older, high oral doses of a compound called N-acetylcysteine, or NAC, for four weeks. NAC is utilized by the body to make glutathione, the body's main naturally occurring anti-oxidant. It has been tested with some success in people with other inflammatory lung problems, including chronic bronchitis, chronic obstructive pulmonary disease and a condition called idiopathic pulmonary fibrosis.


People with cystic fibrosis have a defective or missing version of a protein responsible for, among other things, releasing glutathione into the extracellular spaces. This problem is particularly acute in the airways, where bacteria accumulate. White blood cells called neutrophils are summoned to the lungs to fight infection but stumble into a biological 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 significantly less glutathione than did neutrophils from healthy patients. They theorize that neutrophils must depend on cells around them to maintain their glutathione levels. In cystic fibrosis patients, that help is not forthcoming, and the neutrophils do not function properly.

Four weeks of oral 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 trial participants, who said they felt better during the study.

"The amount of decrease in the inflammatory markers we saw in this preliminary trial was rather astounding," said Conrad. "Many of those who had just completed the study asked if they could continue the treatment." The researchers recently began a 24-week placebo-controlled Phase II trial of NAC in cystic fibrosis patients to confirm their findings. Enrollment for that trial is now closed.

Despite the improvement and the relatively safe profile of NAC, Conrad and Tirouvanziam strongly caution cystic fibrosis patients against self-medicating with NAC or any other drug. Although NAC can sometimes be found as a food supplement, many of these formulations contain little or no active compound, and some even contain a form of NAC that is potentially harmful to cystic fibrosis patients. The NAC that was used in this study is specially formulated for medical use by a Canadian company and is not licensed for sale in the United States.

Other Stanford and Packard Children's researchers involved in the research include Leonore Herzenberg, PhD; Leonard Herzenberg, PhD, and Richard Moss, MD. Teodoro Bottiglieri, PhD, of Baylor's Institute for Metabolic Diseases also contributed to the study. The Stanford researchers are listed as inventors on a provisional patent application covering NAC as a therapeutic agent for cystic fibrosis. Two of the authors (Leonore and Leonard Herzenberg) hold a small amount of equity in BioAdvantex (Mississauga, ONT, Canada), which sells European GMP NAC and provided this NAC for the current study.