Serious Adverse Reaction in Gene Therapy- France & US Halt Trials
October 4, 2002
Gene therapy treatment that appears to cure a rare immune disorder often referred to as "bubble boy disease” or SCID, caused by a mutation of the x chromosome in boys, were suspended in France and the U.S. after a 3 year old child became ill with a leukemia-like disease at Necker hospital, in Paris. This experimental gene therapy treatment had been hailed as the first ever success.
The Washington Post reported: “The incident is a blow to the fledgling field of gene therapy, which had only recently begun to recover its image after the widely publicized death of an Arizona teen in a 1999 experiment. The approach, which seeks to cure diseases by giving patients healthy genes, has been fraught with failure.”
The New York Times reported that Dr. Philip Noguchi, the FDA’s official who oversees gene therapy research acknowledged that while “It is not absolutely a definitive thing, but the preliminary data that we have leads us to suspect that it surely isn’t a coincidence. It’s a sobering experience, but we are doing what should be done.” Some scientists think a definitive determination could take months, if not years, for a definitive determination.
SCIENCE reported that the FDA 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. The FDA’s SCID advisory committee has scheduled an October 10 meeting: http://sciencenow.sciencemag.org/cgi/content/full/2002/1002/0 http://fdaadvisorycommittee.com/FDC/AdvisoryCommittee/TOC.htm
So far all other gene therapy experiments have been unsuccessful. Whether or not genetic manipulation using retroviruses will result in increased rates of cancer is an open question. The Post reported that an FDA official said it would be premature to put a hold on all gene therapy studies involving retroviruses, as many of those studies involve terminal cancer patients getting cancer-fighting genes.
The Times quoted former president of the American Society of Gene Therapy, Savio Dr. Woo, saying: “This has been a spectacularly successful endeavor up to this point. This is a new enemy that we have discovered. We know that there is a theoretical possibility, but it has never been seen before.”
But Dr. W. French Anderson, a professor at the University of Southern California who was among the first scientists to use gene therapy to treat SCID, made the following sobering statement: “We knew it would happen sooner or later.” http://www.nytimes.com/2002/10/04/health/04GENE.html
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http://www.washingtonpost.com/wp-dyn/articles/A40833-2002Oct3.html
THE WASHINGTON POST
Gene Therapy Apparently Leads to New Illness in Boy
By Rick Weiss p. A11
An experimental genetic therapy that had seemed to cure several infants born with a life-threatening immune system disease has apparently caused a leukemia-like syndrome in one of the treated children in France, prompting health officials to suspend all such therapies for that disease in France and the United States.
Officials at the Food and Drug Administration said yesterday they had scheduled an emergency meeting in Bethesda next week, at which scientists involved in the study and other experts will analyze the latest data. One goal is to help the FDA consider whether a wider array of gene therapy studies need to be scrutinized more closely.
The ill patient, a French boy almost 3 years old, is now being treated with chemotherapy in an attempt to kill the blood cells that have begun to proliferate in his body, an ironic twist for a child whose problem at birth was the absence of such cells.
The incident is a blow to the fledgling field of gene therapy, which had only recently begun to recover its image after the widely publicized death of an Arizona teen in a 1999 experiment. The approach, which seeks to cure diseases by giving patients healthy genes, has been fraught with failure. The French treatment had recently been promoted as having delivered the first real cures in the field’s 12-year history.
Despite the setback, scientists yesterday said they suspected that the complication may prove to have been caused by a molecular fluke so unlikely to reoccur that the treatment’s benefits will ultimately prove greater than its risks.
The French treatment still looks “exceedingly promising,” said Joseph Glorioso, director of the Pittsburgh Human Gene Therapy Center and president of the American Society of Gene Therapy. “The field of gene therapy remains vigorous and robust.”
Alain Fisher, the project’s lead researcher at the Necker Hospital in Paris, said he held out hope that the boy would recover, and said the family was being very understanding.
“They are extremely intelligent and courageous. They are very kind people,” Fisher said. “They understood that this was experimental, and they accepted it. I admire them.”
The boy was born with X-linked severe combined immunodeficiency disease, sometimes known as the “bubble boy” disease, caused by a defect in one of the body’s roughly 40,000 genes. Lacking that gene, children cannot produce the white blood cells crucial to fighting off infections. Most die in the first year or so of life.
About 2 1/2 years ago, when he was 2 months old, the boy became one of a few infants enrolled in a new gene therapy study. The experiment involved the use of genetically engineered viruses to deliver copies of the missing gene to young patients’ bone marrow cells. This summer, he was one of five children described in a landmark New England Journal of Medicine article as having been apparently cured.
A total of 11 children from five countries have been treated with the technique, Fisher said. All except the boy are doing well and show signs of having normal immunity.
Fisher said problems first became apparent in the boy in August, when routine tests indicated that his white blood cell count had climbed not just to normal but to abnormally high levels. After a second test indicated even more of a rise, additional tests were done.
Using sophisticated molecular probes, the research team found that the engineered virus, which delivers its genetic payload at random locations within a cell’s DNA, had in at least one cell delivered the curative gene in an awkward location: immediately adjacent to a gene called lmo2 that controls cell division and proliferation.
The team believes that the newly arrived immunity gene disrupted that regulatory gene, predisposing the cell to divide uncontrollably. A second insult — perhaps a viral infection a year or two after the therapy — was probably needed to trigger that division process, Fisher said.
The team notified French authorities about three weeks ago, and then contacted all the families of children they had treated. It’s uncertain how likely such an event is to occur again, Fisher said.
But as a precautionary move, France’s public health agency and the FDA have placed all retroviral-mediated treatments for this immunodeficiency disease on “clinical hold,” a status that precludes further recruitment into trials until the problem is better understood. The hold affects one study underway in London and two that were about to begin in Los Angeles and at the National Institutes of Health in Bethesda.
An FDA official said it would be premature to put a hold on all gene therapy studies involving retroviruses; many of those studies involve terminal cancer patients getting cancer-fighting genes.
Molecular glitches like the one that apparently occurred in the French boy have been considered a theoretical risk of gene therapy since the first such experiments were contemplated in the late 1980s. The first gene therapy experiment took place in September 1990 at the NIH. Since then, thousands of patients have been treated with gene therapy for a wide range of ailments — most of them with retroviruses but increasingly with other gene delivery systems. None has resulted in a case of cancer that experts believed was linked to the treatment, but FDA officials said they are now asking scientists to review their data to see if they may have overlooked such a connection.
Fisher said he remains hopeful that, overall, his treatment will turn out to help more than harm. The only other therapy available for the disease is a bone marrow transplant from a close relative. Unless that transplant is from a perfectly matched sibling (available in only 20 percent of cases), the failure rate is 25 percent, more than twice as high as the complication rate shown so far in the first 11 patients, he noted.
Moreover, Fisher said, the quality of life for bone marrow recipients is not as good as it has been for the children who got new genes.
Yesterday’s announcement of the French complication coincided with the release of a new report on human medical experimentation produced by the Institute of Medicine — a report prompted in large part in response to the death of Jesse Gelsinger, the Arizona teen who died in 1999.
The report calls for increased federal oversight of research involving human subjects, including unprecedented federal oversight of privately funded studies; a revamping of the nation’s ethics review boards that judge proposed experiments; compensation for people harmed in experiments; and the creation of a new federal advisory body to consider issues relating to experimentation on humans.
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