Gene Therapy Experiments Put on Hold
Federal authorities have temporarily suspended three gene therapy experiments -- two of them in Los Angeles -- following news that a third child in a similar French study has developed leukemia and that one of the three has died.
A Food and Drug Administration advisory panel is meeting in suburban Washington today in an effort to determine whether the French cases are an isolated incident caused by the specific gene being used in the therapy or a precursor of problems that will affect all gene therapy attempts.
Experts don’t expect an immediate consensus from the advisory panel, but there appears to be a growing feeling among researchers that the problem is of limited scope and reflects the combination of the virus and gene used by the French. Experiments using other genes have, so far, been free of adverse effects.
Most of the researchers involved will be gathering in Washington March 15 for a separate meeting sponsored by the National Institutes of Health’s Recombinant DNA Advisory Committee. They are scheduled to discuss their results to date. Despite the three leukemia cases, the results have been promising.
The experiments in question have involved treatments for severe combined immunodeficiency disease, or SCID, a potentially fatal genetic disorder that leaves its victims susceptible to life-threatening infections. The best-known example of the disease was David, the Houston “bubble boy” who lived for 12 years in a sterile enclosure to keep infections out.
Dr. Alain Fischer of Necker Hospital in Paris has been treating patients with so-called X-linked SCID, which is caused by a defective gene called GammaC. Fischer put a healthy form of the gene in a modified mouse leukemia virus, which was used to insert the gene into embryonic blood cells that were then infused into the patient.
Fischer has treated 17 patients, and virtually all have shown major improvement if not a cure. But two years ago, Fischer said that two of the patients had developed leukemia, presumably as a result of the treatment.
The FDA temporarily suspended 27 gene therapy trials in the United States but eventually allowed them to proceed again after concluding that there were special circumstances in the cancer victims. Both were below the age of 2 and had received large doses of cells.
In recent weeks, Fischer revealed that one of the two original leukemia victims had died of the disease and that a third child had apparently contracted it. That child, moreover, was older than the first two and received a lower dose of altered cells.
Some experts think the virus inserts the gene at a specific site within the blood cells, called Lmo2, that triggers leukemia.
Concern escalated when Cynthia E. Dunbar of the National Heart, Lung and Blood Institute revealed last month that one of 42 monkeys that had undergone gene therapy experiments using the same virus had developed cancer.
The cancer was found about three years after the monkey was treated, about the same period of time that had elapsed in the French children.
The FDA has not formally announced the suspensions of the gene therapy experiments, but it has temporarily shut down three studies examining treatments for SCID.
One is run by Dr. Harry L. Malech and Dr. Jennifer Puck of the National Institute of Allergy and Infectious Diseases. A second is run by Dr. Donald Kohn of the Keck School of Medicine at USC. The third is run by Dr. Kenneth I. Weinberg of Keck.
Malech and Puck’s study has treated two patients and Kohn’s has treated four. Weinberg has not yet treated any. “Every time we have had patients we wanted to treat, more [news] comes out of France,” Weinberg said.
All three studies will have to revise their consent forms to discuss the potential risks more thoroughly. In effect, that means they will have to go through most of the approval process a second time.
The NIAID and Weinberg studies both involve X-linked SCID. Kohn’s involves a different form of SCID caused by a mutation in the gene for adenosine deaminase, or ADA. Some preliminary evidence suggests that patients in that study are not at as great a risk.
Dr. Claudio Bordignon and his colleagues at the Hospital San Raffaele in Milan, Italy, have successfully treated seven patients with ADA-linked SCID. The first patients treated in Milan are now nearing the three-year mark without incident. More important, a study of their blood cells indicates that the added gene has not been inserted into the hazardous Lmo2 site.
Dr. Robertson Parkman of USC, a member of Kohn’s team, cautions that there is risk associated with most therapies. The French gene therapy death was tragic, but as many as 50% of those treated with the best available alternatives to gene therapy will either die of their disease or suffer lifelong complications from the therapy, Parkman said.
