Genetic Screening : Cystic Fibrosis, Treating the Fetus and Child

by Food and Drug Administration (FDA)

(Page 3 of 4)

While cystic fibrosis carrier tests are being refined, Robert Williamson, M.D., of St. Mary's hospital in London is already combining technologies to diagnose the disease in a fetus in a single day. The diagnostic duo includes chorionic villus sampling of cells surrounding an 8-week fetus (see "Prenatal Peeks") and the polymerase chain reaction, a new method to rapidly copy genes. PCR is applied to a body fluid sample, and the component of interest (such as a gene or marker) is amplified to a level at which it can be detected for a diagnosis.

Says P. Michael Conneally, Ph.D., medical geneticist at the Indiana University School of Medicine and co-discoverer of the marker for Huntington disease: "A pregnant woman comes into St. Mary's Hospital early in the morning. They do a chorionic villus sampling right away, and send the material to Dr. Williamson to do the PCR. They know the results by early afternoon, and the couple is counseled right away."

Like the tests themselves, FDA's role in regulating genetic tests is constantly evolving. For now, tests to detect recently revealed genes or markers are offered by reference laboratories, which are not regulated by FDA unless they market kits to physicians. Physicians send patient samples to these labs, which return the results along with interpretations. Tighter scrutiny of reference labs is beginning. "A new law, the Clinical Laboratory Improvement Act of 1988, will regulate reference labs, except tests for research purposes only. This act will have a tremendous impact on clinical laboratory testing and gene tests," says Tsakeris.

He predicts that screening the general population for cystic fibrosis will be trend-setting. "Cystic fibrosis presents the kind of situation that will emerge for other types of tests. There will be lots of conditions and caveats applied to the use of these tests. It will be a real challenge, and FDA will be caught in the middle. On the one hand, there is a strong push to get new cutting edge tests on the market. Yet, as we all know, as tests are used and experiences collected, tests often do not meet their initial promise. This is true for all clinical tests. For gene tests, the implications will be more profound," Tsakeris says.

Various organizations are rallying to ensure that the mistakes of the past are not repeated in future genetic screens. The National Institutes of Health has called for informed consent, confidentiality, equal access, education and counseling, quality control of reference labs, and voluntary testing as guidelines.

As genetic researchers work their way through human genetic material, their discoveries are expected to spawn many diagnostic tests and, ultimately, treatments. What scientists have learned from experience will enable them to make the best use of this new information. Genetic screening, then, promises to be very much a part of FDA's and the consumer's future.

Treating the Fetus and Child

Blake Schultz' life was saved seven weeks before he was born. Early in 1990, ultrasound revealed a hole in his diaphragm, the muscle sheet dividing the chest from the abdomen. His stomach, intestines and spleen protruded into his chest, squashing his lungs. He would probably have suffocated shortly after birth, were it not for experimental surgery performed by Michael Harrison, M.D., and colleagues at the University of California at San Francisco.

They exposed part of the fetus, opened his left side, gently tucked the organs back into place, and repaired the hole with a patch of Gore-tex, a synthetic material used in warm-up suits. Blake was the first human success, following six others who didn't make it.

Other fetal treatments are more routine. For hydrocephalus ("water on the brain"), a shunt can drain the fluid buildup into the digestive tract, where it exits harmlessly. For too little amniotic fluid caused by a blocked fetal bladder, a catheter can be inserted to drain off the accumulating urine.

"Left untreated, this causes a backup of urine into the fetal genitourinary system, which leads to fetal kidney damage, too little amniotic fluid, and destruction of the lungs?which kills the baby," says Frank Craparo, M.D., who performs such surgery at Pennsylvania Hospital in Philadelphia.

Craparo samples fetal blood to detect anemia and rapidly analyze chromosomes, and can also enter the blood vessels of the umbilical cord to deliver drugs directly to the fetus while bypassing the mother. Called PUBS (percutaneous umbilical blood sampling), the procedure can also be used to provide a lifesaving transfusion when blood between mother and child is incompatible.

"In these cases, the fetus becomes severely anemic, and may die in utero, or be born prematurely," Craparo says. He is working on expanding the capabilities of PUBS. "We will be able to study blood gases, and perhaps see how well oxygenated a fetus is in cases of growth retardation. There are a whole host of tests on the horizon. Anything we can do on adult blood, we may be able to do on a fetus' blood." Still experimental, PUBS carries a risk of 1 to 1.5 percent of harming the fetus.

Treating inherited illness after birth is an option following prenatal diagnosis or newborn screening. Like Blake Schultz, Sam Looper is a trailblazer. One spring morning in 1990, Sam wiggled the big toe of his left foot and, in so doing, made medical history. The 9-year-old suffers from Duchenne's muscular dystrophy, and because of a missing protein called dystrophin, his muscles have been slowly wasting away since toddlerhood.

When the gene behind DMD and its errant protein were discovered in 1986, Peter K. Law, M.D., professor of neurology at the University of Tennessee in Memphis, began reversing DMD-like symptoms in mice by injecting them with immature muscle cells (myoblasts) that produce dystrophin. By 1989, he felt ready to try the approach in humans. To do it as safely as possible, he injected Sam's left big toe with healthy, dystrophin-producing myoblasts from his father.

The boy's body accepted his father's cells, and two months after the transplant, he could wiggle the toe. Still, the approach needs a great deal of refinement to treat major muscles before it enters medical practice.

Sometimes, ideas for new treatments come from existing data. Steve Shak, a molecular biologist at Genentech Inc. in South San Francisco, was intrigued by papers from the 1950s describing a cow enzyme that could dissolve some of the sticky mucus that clogs the lungs of cystic fibrosis patients. But too many patients were allergic to the cow enzyme for it to be developed. Shak applied state-of-the-art genetic technology to locate the human version of the gene that specifies the human version of the enzyme. He hopes that it will clear lungs without triggering allergic reactions, and has applied to FDA to begin testing with patients.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.