For nearly three years, a child with a deadly genetic disease, which left him without functioning B or T cells, has led a relatively normal life. Doctors in France virtually engineered a working immune system for him through gene therapy.1 Early this month, however, researchers revealed that the gene therapy technique used to treat this child's X-linked severe combined immune deficiency (SCID) probably led to a leukemia-like syndrome. The engineered T cells inevitably began proliferating out of control, an event that always loomed as a possibility. The discovery caused the shutdown of similar gene therapy trials.
At an emergency meeting of the US Food and Drug Administration on Oct. 10, however, a panel of experts urged the FDA to resume three recently suspended US trials, saying that the risk of complications appears too low to deprive patients of a technique that has restored immune function in at least eight of 11 patients in France and Australia, and all four patients treated in the United Kingdom. The trials in France, the United States, and Germany are on hold, but the UK trials continue with closer monitoring.
Adrian Thrasher, pediatric immunologist at Great Ormond Street Hospital (GOSH), London, where those gene therapy trials are taking place, says, "The important thing to recognize is that this is an accepted risk--an accepted side effect of this kind of technology. Although this is very unfortunate for the child, given the current evidence in human and animal studies, this [complication] still is going to be a rare event." Treatments at GOSH as elsewhere are restricted to patients for whom the only alternative is a half-matched bone marrow transplant from a parent or sibling--a treatment that carries an estimated 20% mortality rate in the first year. The Biological Response Modifiers Advisory Committee, the panel appearing before the FDA, reportedly mirrored Thrasher's sentiments.2
At the Oct. 10 meeting, Christof von Kalle, associate professor of pediatrics at Cincinnati Children's Hospital Medical Center, presented data on the afflicted 3-year-old's highly proliferating T lymphocytes. A random insertion of the therapeutic gene had localized with LMO2, an oncogene associated with a similar disorder. Alain Fischer, the professor of pediatric immunology at Necker Children's Hospital in Paris who treated that patient, says, "The insertion of the provirus ... is actually very likely regulating the expression of LMO2 because we can find transcripts of LMO2 in patient cells whereas it shouldn't be in such mature T lymphocytes." Fischer and von Kalle, who have examined the cells of treated patients for roughly two years, say the aberrant expression may not be the only cause. They cited as possible contributors the child's genetic predisposition to cancer, and a chicken pox infection that appeared a few days after Fischer first observed elevations in T lymphocytes in April.
Fischer reports that the child has been responding well to chemotherapy. He says they will continue to monitor the cells of this child and other patients to see if they find other random insertions of the provirus near cancer-related genes. If they find others, Fischer says, "Probably that means we should make some modification in the way we do gene therapy for these patients."
Kenneth Weinberg, professor of pediatrics at Children's Hospital of Los Angeles, predicts that the FDA will resume the studies based on discussion at the Oct. 10 meeting. He received FDA approval to begin recruiting patients for his X-linked SCID gene therapy trial just as the FDA was being informed of the adverse effect. Having had prior knowledge of the case, however, Weinberg says they had informed their institutional review board that they would hold the trial as they worked on rewording consent forms.
Although a specific risk has now been noted, the technique still has much potential. The National Institutes of Health will hold a meeting Oct. 29, but Joseph Glorioso, president of the American Society of Gene Therapy, says beyond regulatory approval, which is expected, parents will determine the technique's future use. "If they elect to go forward, they will go forward because they feel like a child with a normal life as opposed to a life of being isolated is worth the risk."
Brendan A. Maher can be contacted at email@example.com.