By Alice Dembner
GAITHERSBURG, Md. - Gene therapy almost certainly caused an illness resembling leukemia in a 3-year-old French boy with "Bubble Boy" disease who had previously been considered one of the few gene therapy successes, scientists and federal officials concluded yesterday.
But because gene therapy appears to have cured nine other French children of the same deadly immune disease, an advisory committee yesterday urged the Food and Drug Administration to allow the resumption of three similar experiments in the United States.
They said that new patients must be told of the potential side effect and be closely monitored. The FDA had halted trials last month after learning of the serious complication in the experiment. Leukemia is a blood cancer in which white blood cells proliferate dangerously. "All the scientific information we have at this point says [the gene therapy] did it," said Dr. Daniel Salomon of the Scripps Research Institute, who led the committee meeting. "All of us are scared about it, and it has implications for the safety of this whole enterprise. However, one serious adverse event doesn't pull the trigger on all these trials."
The FDA typically follows the advice of its advisory committees. At the end of the daylong meeting, Philip Noguchi, the FDA official who oversees gene therapy, said that the leukemia-like symptoms were clearly related to the gene therapy and that the FDA would proceed slowly in deciding its next steps.
The 17-member committee of doctors, scientists, and patient advocates also advised the FDA to disclose the new complications to participants in about 150 other experiments that used the same gene-therapy technique. The experiments, which have involved an estimated 3,000 patients over the last 12 years, all used a specific type of virus, called a retrovirus, to deliver new genes into the body to replace missing or defective genes.
Noguchi said that the FDA has found no evidence of leukemia or lymphoma in other gene-therapy participants, but that officials are still reviewing old reports of side effects. The latest problems were discovered just as the field of gene therapy was recovering from the 1999 death of a teenager enrolled in an experiment at the University of Pennsylvania. Jesse Gelsinger died of a massive immune reaction to the cold virus used to deliver the gene. A different virus caused the French boy's white blood cells to multiply out of control.
Only this spring, French scientists reported the first real success in gene therapy, an apparent cure of four boys with severe combined immuno deficiency, the formal name for the "Bubble Boy syndrome" that had forced them to live in a completely sterile environment. Yesterday, a scientist collaborating with the French said that 9 of the 11 boys treated have developed immune systems.
But one child developed the leukemia-like illness. That boy, who received gene therapy at 1 month old and initially developed the hoped-for immunity, was discovered to have problems at 30 months. After receiving chemotherapy, his cell counts are back to normal and he is doing well, according to Dr. Alain Fischer of Necker Hospital in Paris, who leads the French experiment.
Reviewing blood and DNA samples, scientists discovered that the abnormal multiplication of white blood cells began 13 months after the initial gene therapy. They said the virus inserted the replacement gene close to a gene that regulates cell growth. But they said there were probably other factors
that contributed to his new illness.
"There might be other genetic damage in the child," said Dr. Christof vonKalle of the University of Cincinnati Medical School, who presented data he had reviewed for Fischer.
Kalle also said the child's bout with chickenpox, his family history of cancer, and his young age at transplant might have contributed. Because studies in mice had indicated that gene therapy might cause cancer, patients in experiments have long been informed of the possible risk. But this is the first confirmed case.
Patient advocates were divided about how the FDA should proceed. The Council for Responsible Genetics of Cambridge called for a moratorium on all gene-therapy experiments. And Abbey Meyers, president of the National Organization for Rare Disorders, said, "If there is other treatment, then maybe children shouldn't be exposed to this risk."
But the grandmother of an immune-deficient boy who had failed other treatments urged the FDA to "consider the risk of no treatment." And Paul Gelsinger, Jesse's father, praised the FDA for its open discussion of the problems.
"Bubble Boy" syndrome and similar severe immune deficiencies have been successfully treated with bone marrow transplants if an exact match can be found. In cases where there isn't an exact match, the transplants fail in 25 to 40 percent of cases.
Printed by the Boston Globe, 11 October 2002
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