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FDA calls off gene therapy experiments after patients develop cancer
By The Washington Post
Friday, March 4, 2005
WASHINGTON -- The Food and Drug Administration has suspended several U.S. gene therapy experiments after learning that a third child who underwent treatment in France has developed cancer as a result, a development that has cast a pall over the struggling research field.
Adding to the gloom, researchers are scheduled to report today that a monkey has died of cancer caused by a gene therapy experiment six years ago. That suggests the treatments may carry long-term as well as near-term risks, said scientists who will be discussing the issue at an FDA meeting today.
The events are the latest in a series of setbacks for a field that a decade ago seemed poised to revolutionize medicine by replacing defective genes with healthy ones, fixing the molecular underpinnings of disease instead of simply treating its symptoms.
After thousands of efforts, the treatments appear to have cured only about a dozen patients, all of them children in Europe who were born with a severe immune system disorder. With three of those children now having developed cancer from the treatments and one recently dying of it, even the field's most ardent supporters are discouraged.
"We want to continue, but of course there is a safety issue," said Alain Fischer, of the Necker Hospital in Paris, the leader of the French study.
The details are to be discussed at today's meeting of the FDA's Cellular, Tissue and Gene Therapies Advisory Committee in Rockville, Md.
The latest cancer case appeared a few weeks ago, in a 3-year-old boy Fischer treated in the summer of 2002. Like the other children in the study, the boy was born with X-linked severe combined immune deficiency, or X-SCID. The disease, which affects only boys and disables the immune system, was made famous in the 1970s by David Vetter, the Texas "bubble boy," who lived his 12 years in a plastic tent to protect him from everyday infections that for him could prove fatal.
The only other way to cure the disease is a perfectly matched bone marrow transplant, but such matches are rare and recipients of unmatched transplants don't fare well. The experimental alternative involves infusions of mouse viruses engineered to carry the immune system gene that patients lack.
The viruses infect the patients' immune system cells and in so doing deliver the needed gene. But the viruses sometimes disturb healthy genes -- including genes that, when disrupted, can cause cancer.
The first case arose in September 2002, triggering an international suspension of all similar experiments. A second treated boy was diagnosed with cancer that December. Both had been treated as infants and developed leukemia about 2 1/2 years later.
Although both appeared to respond well to chemotherapy, one of the boys died last October, after the experiments were resumed with new safeguards.
The latest case, a boy who was treated as an 8-month-old in 2002, was diagnosed about five weeks ago -- just a couple of weeks after the team had begun gene therapy on its newest patient, Fischer said in a telephone interview. He said he immediately stopped the study again and, although he is not regulated by the FDA, notified the U.S. agency.
The FDA does not generally tell the public about clinical trials it has put on hold, and officials declined to say this week what actions they had taken in light of the latest diagnosis. But U.S. researchers involved in two experiments similar to the one in France told The Washington Post that the agency had recently directed them to suspend their studies. One experiment is being led by Harry Malech and Jennifer Puck at the National Institutes of Health (NIH) in Bethesda, Md., who have treated two patients so far. The other, led by Donald Kohn of the University of Southern California, has enrolled four patients.
Fischer said the recently diagnosed boy in France is undergoing chemotherapy and emphasized that the other cancer survivor and the other dozen or so children treated previously all are doing well.
"They can cope with infections. That tells us efficacy is there," Fischer said. "There is a future in gene therapy."
But in light of the monkey's case, Fischer and others acknowledged it will be many years before the final verdict is in.
The monkey, whose September death has not been previously publicly disclosed, was one of 42 being watched by NIH scientists for delayed effects of gene therapy. It is the only one to have developed cancer so far, said study leader Cynthia Dunbar, of the National Heart, Lung and Blood Institute. But with an average follow-up of only about three years so far, it's too soon to know how many might show delayed effects, she said.
Unfortunately, she added, most research teams kill their animals less than a year after using them in gene therapy experiments.
"It's extremely expensive, but this shows how important it is" to study the animals longer, Dunbar said, who called the fatal cancer "very concerning."
In both the human and monkey experiments, the mouse virus used -- known as a murine retrovirus -- is the most common means of delivering DNA in gene therapy experiments. Its predilection to interact with genes that can cause cancer has led many scientists to look for better delivery systems.
Among the most promising, several scientists said, are genetically modified "lentiviruses" -- including the human immunodeficiency virus (HIV), which causes AIDS -- in part because they appear less likely to trigger the kind of cell replication that adds up to cancer.
To date the FDA has approved three human studies involving infusions of genetically engineered lentiviruses, according to NIH records -- all of them restricted to patients who already have AIDS.
Mark Kay, a professor of pediatrics and genetics at Stanford University and president-elect of the American Society for Gene Therapy, said he remains hopeful that gene therapy will prevail.
"This is a devastating side effect," he said of the cancers, speaking for himself and not for the society. "But taking a disease that is pretty much fatal ... if you can get a 60 or 70 percent cure rate, you have to balance that out."
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