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Gene Therapy Defended Despite New Setback

Side effect in French boy triggers suspension of four studies

FRIDAY, Oct. 4, 2002 (HealthDayNews) -- Gene therapy researchers today defended their field despite news that a mysterious leukemia-like side effect has forced the halt of four trials of the treatment in children with deadly immune system defects.

Health officials in the United States and Europe took that step last month after a 3-year-old boy in France undergoing gene therapy to cure a condition called X-linked severe combined immunodeficiency disease, or X-SCID, experienced runaway growth of his immune system's T cells. The boy is receiving chemotherapy and appears to be doing well, people familiar with the case said.

Nine other children in the French study also cured of their disease have not shown signs of the same side effect, according to the American Society of Gene Therapy. The study is being led by Dr. Alain Fischer of the Necker Hospital in Paris.

Researchers are not certain gene therapy is to blame for the reaction, though it seems likely. Children with X-SCID -- sometimes called "bubble babies" -- have virtually no T cells. So in the absence of treatment, the boy would not have developed runaway production of them. Moreover, scientists have known that the corrective gene, which enters the body hitched to a retrovirus, could in theory lodge in or next to a cancer-promoting gene and cause trouble.

"We knew the risk that this therapy carried with it, and we've always presented that to all our patients," said Dr. Fabio Candotti, a gene therapy expert at the National Institutes of Health and leader of one of the suspended studies.

Dr. Mark Kay, a Stanford University gene therapy expert, said it's plausible the French boy's condition wasn't a result of his treatment. "The thing that's probably most important is to see where [the corrective gene] inserted." Kay is running a study of gene therapy in adults who have the blood-clotting disorder hemophilia. That trial is not affected by the stoppage.

Candotti called the latest problem a temporary setback for gene therapy and said it wouldn't undermine its long-term viability. Nearly three dozen children have undergone the procedure for SCID, and roughly 1,000 people have had gene therapy using retroviruses. Until now, none had developed the leukemia-like condition.

The first gene therapy trial a decade ago attempted to correct a form of SCID in which the patient did not make enough of a key immune enzyme. The method has been applied to a wide range of other ailments, from head and neck cancers to heart problems. But to date, it has led to cures only in children with SCID.

Because gene therapy for SCID babies involves a one-time treatment, pausing the studies simply means that no new patients will be enrolled in the trials. Those who've already received the therapy will be monitored for signs of trouble.

The studies involved children who failed bone marrow transplants and therefore had no other chance of surviving their disease. Although children who receive marrow from a sibling with a perfect cell match have an excellent chance of success, only about 20 percent to 25 percent of patients are so well-paired, Candotti said. For the rest, even those with a partial match, the death rate is 20 percent or worse.

"One would say that [gene therapy] is more successful and less toxic" than bone marrow transplants for 75 percent to 80 percent of patients, Candotti said.

The U.S. Food and Drug Administration will take up the fate of the stalled gene therapy trials at a meeting next week. Two of the three U.S. studies have not enrolled any patients yet and involve a different form of SCID from the French research.

Dr. W. French Anderson, who helped lead the first gene therapy trial in the United States, said he supported the decision to put a hold on the studies "until we can figure out what happened in France."

Anderson, of the University of Southern California's Keck School of Medicine in Los Angeles, said regulators were concerned about precisely such a complication when he and his colleagues were preparing to conduct their study a decade ago.

However, they could find only three cases of the leukemia-like condition in hundreds of lab animals, and those three episodes occurred in monkeys exposed to extreme conditions of immune suppression. "Because [the risk] was low, that's the reason the FDA and the NIH let us go ahead," Anderson said. Even so, he added, "We knew it was going to happen, and sadly it has happened."

Anderson remains confident in the future of gene therapy. Yet he said the latest incident is a warning to scientists who might try to apply it to conditions that aren't life-threatening, like baldness. "I've been arguing this for 30 years: Gene therapy is a very powerful technology, and it should not be used for any other purpose but for the treatment of serious disease," Anderson said.

Dr. Jonathan Goldsmith, vice president of medical affairs for the Immune Deficiency Foundation in Towson, Md., backed the decision to halt the gene therapy trials until scientists determine what caused the French boy's illness. "It could be gene therapy itself, it could be something to do with the patient, or it could be a combination," he said.

But Goldsmith said the investigation must be quick. Roughly one in 75,000 American babies is diagnosed with SCID each year. If the suspension lasts six months, 25 to 50 infants might be born with disease in that time. Both gene therapy and bone marrow transplants "should be done as soon as possible," Goldsmith added.

The Institute of Medicine released a report yesterday calling on Congress to require researchers in both public and private institutions to better safeguard people enrolled in clinical trials. The study was commissioned after the death in 1999 of Jesse Gelsinger, 18, who had been participating in a gene therapy study at the University of Pennsylvania.

What To Do

To learn more about gene therapy research, visit MEDLINEplus. For more on SCID, try the Immune Deficiency Foundation.

SOURCES: Fabio Candotti, M.D., head, immunity disorders section, National Human Genome Research Institute, Bethesda, Md.; W. French Anderson, M.D., director, gene therapy laboratory, University of Southern California Keck School of Medicine, Los Angeles; Mark Kay, M.D., Ph.D., professor of pediatrics and genetics, Stanford University School of Medicine, Palo Alto, Calif.; Jonathan Goldsmith, M.D., vice president for medical affairs, Immune Deficiency Foundation, Towson, Md.
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