Novel Therapy for Cystic Fibrosis Enters Clinical Trials At Stanford.

Medical, Health & Education Writers

STANFORD, Calif.--(BW HealthWire)--March 12, 2001

Stanford University Medical Center researchers are testing a novel inhaled therapy to help cystic fibrosis patients avoid progressive lung damage that can lead to respiratory failure. Richard Moss, MD, is the principal investigator for the nationwide clinical trial to test whether gamma interferon - an immune system modulator - can reduce chronic airway inflammation in cystic fibrosis patients and thus potentially help them lead healthier, longer lives.

The approach would offer a better alternative to standard treatments, which strive to prevent inflammation by fighting bacterial infections and breaking down the thick mucous that clogs the lungs of sufferers. "Antibiotics and mucous thinners haven't really delivered the knockout punch we're looking for," said Moss, professor of pediatrics and director of Stanford's Cystic Fibrosis Center. "But this trial represents an entirely new approach to cystic fibrosis therapy. We're really excited."

The trial marks the first time researchers have attempted to prevent lung damage by controlling the patients' immune response to infection. It also employs a novel delivery mechanism for gamma interferon, which belongs to a class of molecules called cytokines. By administering the molecule as an inhalant, the researchers hope to confine its effect to immune cells in the lung and avoid adverse side effects associated with injections of the compound.

Cystic fibrosis is the most common fatal genetic disease among Caucasians in the United States. About 30,000 people in this country suffer from the disease, which is characterized by abnormally thick mucous that clogs the lungs and traps inhaled microbes and irritants. The sticky mucous also fosters a warm, moist environment perfect for bacterial growth. The chronic infection and inflammation associated with the disease damages the lungs and can lead to death in young adulthood. Nearly 1,000 new cases are diagnosed each year and no cure exists.

Gamma interferon is a versatile molecule that modulates the response of many different immune cells in the body; it's already used clinically to treat several different diseases. Moss has previously shown that immune cells from cystic fibrosis patients produce less gamma interferon when stimulated than do cells from healthy subjects. Other researchers have found that the severity of lung damage in cystic fibrosis patients correlates inversely with the amount of gamma interferon they produce - less gamma interferon means more damage.

"It's really one of the most important cytokines that the body uses to fight off infection," said Moss. But gamma interferon's ability to affect cells throughout the body makes it difficult to restrict its activity when used clinically - especially when delivered by injection. However, the nature of cystic fibrosis makes it possible to limit the effect of the molecule.

"When interferon is injected it has a moderate amount of toxicity throughout the body and it sometimes causes a flu-like reaction. However, cystic fibrosis patients inhale it directly into the lungs and it doesn't go into the rest of the body," Moss said. In preliminary tests, patients with tuberculosis and asthma tolerated the inhaled gamma interferon well, and there was little evidence that it was active in the bloodstream, he added.

Researchers hope gamma interferon will block the destructive cycle of infection and inflammation in the lungs of cystic fibrosis patients by simultaneously stimulating the infection-fighting properties of one type of immune cell (lung macrophages) and suppressing the activity of another (neutrophils) that cause airway inflammation and destruction.

Researchers at Stanford administered the first dose of gamma interferon less than three weeks ago. Eventually 60 cystic fibrosis patients at eight medical centers around the country will participate in the double-blinded, phase-II trial structured to test the safety and efficacy of gamma interferon. Approximately one-third of the patients will receive a placebo, and the remaining two-thirds will be split into two groups to test two different dosages of gamma interferon. Patients will be treated three times per week over a period of three months, and researchers will monitor lung function as well as the extent and severity of infections.

Other participating centers include: Johns Hopkins School of Medicine, Harvard Medical School, Denver Children's Hospital, University of Washington Medical Center, Children's Hospital Medical Center of Cincinnati, University of North Carolina at Chapel Hill Medical Center, and Case Western University's Rainbow Babies and Children's Hospital.

Funding for the study was provided by InterMune Pharmaceuticals, Inc.; the National Institutes of Health; the Cystic Fibrosis Foundation; the Ross Mosier Fund; and the Hedco Foundation. InterMune markets the gamma interferon used in the trial under the trade name ACTIMMUNE(r).