Citing Illnesses, FDA Halts Gene Therapy Trials

The Food and Drug Administration on Tuesday suspended 27 gene therapy trials -- nearly half of those now underway in the United States -- after the agency learned that a second French child had developed leukemia after receiving the promising, yet highly experimental, treatment.

The agency had halted three trials in October following the revelation that one child had developed the potentially fatal form of cancer. The suspension was broadened Tuesday “because of unanswered questions about what is going on,” said Dr. Philip Noguchi, in charge of gene therapy issues at the FDA.

Noguchi cautioned, however, that participants in the programs should not be unduly alarmed, because an intensive study has revealed no other cases of leukemia outside the French program.

Three trials at Childrens Hospital Los Angeles have been halted as a result of the “clinical hold” initiated by the FDA, and that is an “appropriate action,” said Dr. Donald Kohn, who leads one of them. “We need to find out why this has happened twice,” he added.

An emergency meeting has been called for Friday by the Office of Biotechnology Activities at the National Institutes of Health to discuss the problem. The FDA has also scheduled a meeting Feb. 28, at which some of the trials could be reinstated.

The first leukemia case increased concerns about potential risk from gene therapy, but proponents argued that it represented only an isolated problem. The occurrence of a second case in such a small group of children, however, has raised concerns substantially higher.

Critics argue that researchers have charged into human trials without first fully exploring potential risks in tests on animals, and even some proponents now concede that further animal studies may be necessary.

Those concerns were first brought forward after the 1999 death of 18-year-old Jesse Gelsinger, who suffered a violent reaction to a gene therapy treatment at the University of Pennsylvania. Critics charged that Gelsinger’s death was needless because he suffered from a mild genetic disorder and had it under control with drugs and diet. Several gene-therapy trials were halted after his death, but they were allowed to resume the following year.

“I have no doubt that the death of Jesse Gelsinger is going to lead to nothing but a cautious, go-slow approach,” said ethicist Arthur Caplan of the University of Pennsylvania. “As a society, we’re more nervous about genetics” than about any other form of medical therapy, he said. “Maybe it’s time to go back to animals and see what we can establish there” about the causes of the leukemia, he added.

Kohn said that despite the new setback, he remained hopeful for the field. “We have to remember that seven of the 10 kids [in the French trial] were cured of an otherwise fatal disease” without developing problems, he said. “There is tremendous promise in gene therapy, but this specific approach may be a problem, and we may need to look for other ways to use gene therapy in this disease.”

Gene therapy seeks to replace defective genes with healthy ones to cure a variety of diseases, from genetic disorders to HIV infections and cancers. Researchers believe it is the only potential treatment for many inherited diseases.

The two children who developed leukemia were part of a group of infants with a disease, known as X-linked severe combined immune deficiency, treated with gene therapy by Dr. Alain Fischer and his colleagues at the Necker Hospital for Children in Paris. The illness is commonly known as “bubble boy” disease.

The children have a defective gene, called GammaC, that prevents them from developing immunity against infectious diseases. Untreated, such children die within the first year of their lives due to severe and recurrent infections. Some victims are successfully treated with a bone-marrow transplant from a sibling who is a perfect match, but such matches are not often available.

Fischer used a so-called retrovirus to insert a healthy copy of the gene into the children’s hematopoietic (blood-forming) cells. His trial was widely hailed because nine of the children were apparently cured of the disease and were able to go home.

But in October, one of the children, now 3 years old, was found to have leukemia. Childhood leukemia has a 90% cure rate with chemotherapy, and the child is reportedly doing well under treatment. The second child is also being treated, and doctors say he is doing well.

But U.S. officials concluded that the disease was a direct result of the gene therapy, and they halted three U.S. trials that had very similar protocols. That included the trials at Childrens Hospital. Kohn said researchers there voluntarily suspended a third trial -- involving treatment for pediatric AIDS -- that had not yet begun.

Now that a second leukemia case has been discovered, the FDA halted all trials in which retroviruses are being used to insert genes into hematopoietic cells.

The American Society of Gene Therapy said Tuesday that it will organize an ad hoc committee to conduct a comprehensive review of such trials in an effort to understand whether the leukemia problem is unique to the French trial or a more common problem.

Some researchers have argued that gene therapy has a potential for harm because the retroviruses insert the gene into the host cells at random locations. Some insertions could trigger carcinogenic genes or produce other adverse effects.

Others suspect that GammaC itself is the problem. The gene is the blueprint for a growth-factor receptor that can stimulate a proliferation of cells, and inserting it into cells may trigger cancerous growths.