Health authorities in several countries are responding to a serious adverse event in a gene therapy trial. A disease resembling leukemia has appeared in a child treated by clinicians under Alain Fischer and Marina Cavazzana-Calvo at the Necker Hospital in Paris. They were hailed around the world in 2000 after they used a modified retrovirus to give healthy genes to two boys, apparently curing them of an inherited disease. Concerned that the therapy itself might have caused leukemia in one of 10 patients they have treated, however, the French group halted its trial in September and urged colleagues using retroviruses to hold off while the risks are assessed.
Fischer says his group recognized the importance of the case "exactly one month ago" but wanted to explain it to patients before going public. The French team quickly sent letters to other gene therapy groups using retrovirus vectors, which are used in a small fraction of gene therapy trials. Experts had realized that retrovirus-based therapy might cause cancer, he explains, but the risk seemed very small. When the French team's warning reached the National Institutes of Health (NIH) in Bethesda, Maryland, a planned six-patient trial was put on hold. At least two other trials have been suspended.
The French trial was designed to give early treatment to children with a fatal disease, severe combined immunodeficiency (SCID), caused by a mutation on the X chromosome (ScienceNOW, 28 April 2000). During a routine check of their fourth patient last spring, the French group noted an excess of a particular type of T cell. In late August, the count had climbed drastically--triggering a decision to hospitalize the patient and suspend the trial. Molecular studies revealed that all the T cells contained a DNA signature from the site where the retrovirus vector had integrated itself into the host's genome. This site is within the coding region of a gene that's "aberrantly expressed" in a form of childhood leukemia, Fischer says. Other factors, including a history of cancer in the child's family, may have contributed to the disease.
The U.S. Food and Drug Administration has organized an emergency session of its Biological Response Modifiers Advisory Committee, set for 10 October, to consider what steps should be taken next. And NIH's Recombinant DNA Advisory Committee is preparing a broad review of the case at its next meeting, scheduled tentatively for 4 to 6 December.