MEDICINE / CYSTIC FIBROSIS : Promising New Therapy for Lung Congestion May Check Fatal Disease

Researchers are poised to begin human trials of a new therapy for cystic fibrosis that promises to reduce the lung congestion that is the most damaging aspect of the inherited disorder.

The new therapy, which could be in widespread use in as little as three years, would provide a major benefit for the 30,000 Americans who suffer from cystic fibrosis, which usually is fatal by the mid-30s.

North Carolina researchers report today in the New England Journal of Medicine that treating the nasal passages of cystic fibrosis patients with common cellular components called nucleotide triphosphates can reverse some of the effects of cystic fibrosis--a strong indication that it can do the same in the lungs. But now they have to find out if it is safe to spray the compounds into the lungs.

The researchers have already successfully sprayed it into their own lungs and expect to expand those safety trials to others within a month. Tests of the drug’s efficacy could begin within a year, said pulmonologist Michael R. Knowles of the University of North Carolina.

The new paper represents “a remarkable piece of science” that “has a potential to have a tremendous impact on this condition,” said Claude Lenfant, director of the National Heart, Lung and Blood Institute.

“Maybe cystic fibrosis no longer has to be a fatal disease,” added Robert J. Beall, medical director of the Cystic Fibrosis Foundation.

The disease is marked by a buildup of mucus in the lungs and the upper respiratory tract that impairs breathing and leaves the victims susceptible to infections that destroy lung tissues. It also affects the pancreas in about 75% of victims, blocking secretion of enzymes necessary for digesting and absorbing fats in the diet. The new therapy would not treat pancreatic symptoms.

The symptoms result when cells in the lung absorb too many sodium ions and fail to secrete chloride ions. As a result, the cells retain too much water and the mucus that normally cleanses the lungs becomes unusually thick and gummy.

Knowles and his colleagues reported last year that administration of amiloride, a diuretic normally used to treat high blood pressure, could reduce the cells’ intake of sodium and thereby partially reduce the severity of symptoms. They are now studying the effectiveness of that drug in preliminary trials on 300 patients.

The new therapy with nucleotide triphosphates would complement the effects of amiloride by stimulating secretion of chloride, so that mucus would have the proper consistency. Tests in lung cells grown in the laboratory show that this is precisely what happens, Knowles said.

In the study reported today, Knowles and his colleagues bathed nasal tissues of nine healthy adults and 12 cystic fibrosis patients with saline solution containing a dilute concentration of two nucleotide triphosphates. Those compounds are two of the raw materials used by cells to synthesize DNA (deoxyribonucleic acid, the genetic blueprint of life).

Knowles found that the two compounds stimulated the nasal cells to secrete more chloride, and that the effect was more pronounced in the cystic fibrosis patients.

Knowles noted that his team has been studying nasal cells for more than a decade as a model for lung cells and has found that, “at least in all of the studies we have done before,” the nasal cells behave exactly as lung cells would. This makes him confident that the treatment will also be effective in lung cells.

The primary problem now is to determine the safety of the treatment. Knowles noted that the nucleotide triphosphates have been used for many years in France as a nasal spray for treating colds. Their efficacy for that purpose has never been proven, he said, “but they have been used for a decade without causing lots of problems,” suggesting they are relatively benign.

Some of Knowles’ colleagues have already begun studying the compounds in dogs. That should give some information about safety but not about efficacy because neither dogs nor any other animals develop cystic fibrosis.

Talking about spraying the compounds into their own lungs, Knowles said, “At some point, you have to take a leap of faith and use (them) on humans for the first time. We’ve already done that.”

He added, “If we don’t run into a lot of side effects, we could get into (efficacy trials) within the next year.” He said that the group has just been through the same process with amiloride and that, “with that experience and practice, we should be able to move fairly quickly.”