Cystic Fibrosis : Treating CF, Gene Therapy

by Food and Drug Administration (FDA)

(Page 3 of 4)

All CF Mutations Are Not Equal

Checking for an errant CF gene may be easy, but interpreting the results may not be. Researchers are finding that different CF mutations cause different degrees of sickness. Alex Deford probably had two copies of delta F508, the most common and one of the more serious mutations that can cause CF. But a researcher in the laboratory of Francis Collins, the co-discoverer of the CF gene, has a milder case of CF because he inherited the delta F508 mutation as well as a different one.

This young man must perform postural drainage on himself and take antibiotics and digestive enzymes, but he also plays the trumpet, bikes, and sings. Still, a respiratory infection can send him to the hospital for a week or longer. Clinicians are finding that some people who have frequent bouts of pneumonia and other respiratory infections actually have CF.

Some people with CF may not even have lung or digestive symptoms. Aubrey Milunsky, D.Sc., Director of the Center for Human Genetics at the Boston University School of Medicine, found that some men who were referred to him because they were having difficulty fathering a child actually had CF. In examining x-rays that had been taken as part of a standard fertility work-up, Milunsky noticed the men lacked the vas deferens, the paired tubes that deliver sperm from the body. Knowing this is a symptom in 90 percent of men with CF, Milunsky tested their genes and found they had inherited CF.

"Cystic fibrosis is not a simple single mutation to look for," says Margaret Wallace, Ph.D., assistant professor in the division of genetics in the department of pediatrics at the University of Florida in Gainesville. "There will be a lot of problems in doing the diagnosis and giving an idea of what it means," she adds.

Treating CF

CF symptoms are controlled with a number of drugs. Antibiotic drugs combat infections to which CF patients are prone, including Pseudomonas aeruginosa bacteria, a type of microbe that is attracted to the sticky mucus in the lungs. The combination of animal enzymes, called Viokase, that Alex Deford took regularly is still used today by CF patients. It is approved as a prescription digestive aid for CF patients and others with pancreatic insufficiencies. Combined with a high-calorie diet, this enzyme preparation aids digestion, helping the patient to maintain weight.

Many patients also take anti-inflammatory prescription drugs, such as ibuprofen (Motrin and others), prednisone (Deltasone, Winpred, Orason, and others), and naproxen (Anaprox, Naprosyn and others).

The drug amiloride (Midamor, Moduretic), introduced in 1967 and approved as an adjunct to treatment with some diuretic drugs, is now being tested as a treatment for CF. Scientists believe amiloride thins lung secretions by blocking sodium uptake by lung cells. Clinical studies are under way to assess amiloride as a CF treatment alone, and in combination with the biological products adenosine triphosphate (ATP) and uridine triphosphate (UTP). (ATP and UTP are components of the nucleic acids DNA and RNA.)

Other investigational products are aimed at tempering the body's immune response to lung infection, which can be excessive. One such product is deoxyribonuclease. The March 19, 1992, New England Journal of Medicine reported that in a pilot study, this protein biologic given in an aerosol helped clear the lungs of 16 adult CF patients. It is being tested in 900 CF patients at 50 medical centers in the United States.

Gene Therapy

FDA has designated recombinant cystic fibrosis transmembrane conductance regulator (the gene's protein product, abbreviated CFTR) as well as gene therapy as orphan products. This gives their sponsors special incentives because they are developing products for a condition affecting relatively few people.

The first human gene therapy study of CF got under way last April 17 at the National Heart, Lung, and Blood Institute after FDA gave the go-ahead the previous day. An engineered cold virus (adenovirus) was introduced into the cells lining the nose and airways of a 23-year-old man with CF. The virus was altered to carry the normal CFTR gene and lacks the genes to cause a cold and to replicate.

The research was the first use of gene therapy for a common genetic disorder and the first use of a cold virus to transport genes. The study includes 10 patients age 21 or older who have mild to moderate CF symptoms.

Previous experiments in rats indicated that replacing the CF genes in just 10 percent of the lung lining cells improves lung function. However, because the genes go to the patients' lungs but not their sex cells, CF can still be passed to the patients' children.

New knowledge of CF is coming so fast that the goals of carrier screening may change even before the tests are cleared for marketing.

Soon, detecting the gene for CF may be a way of finding who needs treatment, as early as possible, just as is presently done for high blood pressure and elevated blood cholesterol. Says Wallace, "CF research is moving so quickly, with a lot of hope for treatment in the near future. It will be treatable, and possibly easily."

About the Author

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