Brave New Babies

By LEON JAROFF

Even before Andrew Gobea was born, doctors knew his future would be clouded. Prenatal tests showed he had inherited a set of defective genes that would % leave him defenseless against infections. Had he been born 10 years earlier, he could have survived only in a sterile environment, as did David, the famous "Bubble Boy," who died after 12 years inside a sealed plastic enclosure. Andrew, however, has a chance to lead a normal life. In a new test of gene therapy, doctors at Childrens Hospital in Los Angeles, using blood extracted from his umbilical cord moments after he was born, separated out some white cells and inserted a new gene into them. The altered cells were injected into Andrew's body four days later in what could become part of a remarkable medical milestone: the first attempts to cure a disease by gene therapy.

Andrew was one of three youngsters with Severe Combined Immunodeficiency treated with the new technique in the past two weeks. Doctors at the University of California at San Francisco performed an operation identical to Andrew's on Zachary Riggins, a three-day-old infant. And at the National Institutes of Health in Bethesda, Maryland, an 11-year-old girl underwent a similar procedure. These three cases mark an important new phase in the rapidly expanding field of gene therapy. Earlier experiments involved inserting beneficial genes only to treat disease, not to cure it.

The new work is based on the landmark experiment performed in 1990 by NIH Drs. W. French Anderson, Michael Blaese and Kenneth Culver on two Ohio girls, ages 4 and 9. Neither child was producing ADA, an enzyme that rids the bloodstream of harmful metabolic products. The absence of ADA can cause SCID by allowing toxic substances to accumulate and destroy immune-system cells. Both children had been kept alive by weekly injections of PEG-ADA, a costly synthetic enzyme, but neither was in good health.

In the first approved gene-therapy trials, the pioneering NIH team extracted immune-system T cells from the Ohio girls, inserted normal ada genes into the cells and reinjected them. As the team had hoped, the T cells began churning out natural ADA, enabling the children's immune systems to function effectively. While that result marked the first successful treatment by gene therapy, it was not a cure; the altered T cells die out after several months, and the little patients must return to the NIH periodically to repeat the procedure.

Seeking a cure, researchers have now focused on so-called stem cells -- long-lasting cells that continually give rise to fresh blood cells. If ADA genes could be inserted into the parent stem cells, the scientists reasoned, the genes would be passed on to all newly formed immune cells, including T cells, and the patient would be ensured a permanent supply of the enzyme. But stem cells are rare, and most of them reside in the bone marrow.

In his latest experiment at the NIH, Blaese administered a drug to one of his two original Ohio patients that coaxed some stem cells out of the bone marrow and into her bloodstream. Extracting blood, he painstakingly separated out the rare stem cells, inserted normal ADA genes into their DNA and injected the cells back into the girl's bloodstream, hoping that they would migrate back to the marrow and take up permanent residence.

While stem cells are scarce and difficult to extract in children and adults, they are plentiful in umbilical-cord blood. For that reason, the new gene- therapy technique is particularly applicable to newborns. And the parents of both infants involved in this month's California experiments had ample warning that they would need the new treatment.

Although Richard and Lori Riggins, of Exeter, California, have a normal four-year-old daughter, a son born to them in 1991 was diagnosed with SCID at the age of four weeks, and ever since has required treatment with PEG-ADA to survive. His disorder was evidence that both his mother and father, while healthy themselves, carried a recessive gene for SCID. This meant that any of their offspring would have a 1-in-4 chance of being stricken with the disease. The outlook was equally gloomy for Crystal Emery and Leonard Gobea, from California's Imperial Valley; their first child died from SCID at five months.

Aware of the risk, both mothers chose to have amniocentesis after becoming pregnant again last fall. The test results showed that neither fetus was producing ADA and that the babies would have SCID. It was then that Dr. Diane Wara, the pediatric immunologist who had treated the Rigginses' other child, suggested the stem-cell trial. Lori Riggins was easily convinced. "You only get a once-in-a-lifetime chance to get large amounts of stem cells," she says. "That's at birth, and we didn't want to pass up that chance."

Emery and Gobea also agreed to have their son be part of the experiments. Immediately after Andrew was born, the obstetrician snipped his cord and drew out the umbilical blood. She rushed it to Childrens Hospital in Los Angeles, where a team led by Drs. Donald Kohn and Kenneth Weinberg separated the stem cells and endowed them with normal ADA genes. Then the newly equipped stem cells were injected into the baby's bloodstream. Two days later, Wara went through the procedure on Zachary Riggins in San Francisco, after his stem cells had been shuttled to Kohn and Weinberg in Los Angeles for genetic engineering.

To guard against the possibility that the gene therapy will not work, doctors will initially treat both infants with weekly injections of PEG-ADA. "We have no intention of letting these children get sick while we're waiting to see if the stem cells ((become functional))," says Wara. "When we see that this has happened, then we will start withdrawing the enzyme replacement." But will it happen? "My personal hunch is that this is going to benefit these two children," says Kohn. "If it does, then we can go on to more common diseases."

With reporting by David S. Jackson/San Francisco and Larry Thompson/Bethesda