2005, third adverse event in Paris! (Dritter Leukaemie-Fall
in Paris!) Initiated: Jan. 24,
2005 You are welcome to send your
feedback by email to Sandro
Rusconi stained white cells
smear, with leukaemic cells Bad news strike back a third
2000 Alain Fischer published his first results on the
treatment of young patients suffering from a rare condition
due to a single gene defect. The medical team has meanwhile
pursued the same type of investigations on 11 patients. 10
therof had beed successfully cured. By October 2,
2002 the trial has been voluntary suspended by after the
team reported a leukemia-like condition emerging in one of
the patients. The purpose of this page is to keep interested
people constantly informed about the development and the
aftermath of this adverse event. The AF team has managed the
case with extreme professionality and transparence and
reported at the annual meeting of the European society for
gene therapy (ESGT, Antibes, 16-20 Oct 2002). The hope at
that time was that this ought to be just an erratic
January 14, 2003, we unfortunately hear that a
second case similar to the one reported in October
has emerged in the cohort of treated patients. Although the
role of insertional mutagenesis as a sole causative agent
for these cases remains to be elucidated, the picture is
getting somewhat worrysome. By
January 24, 2005, a third case of T-cell
hyperproliferatzion is publically disclosed. This page is
dedicated to that third case and its consequences and
reactions. Media Box 03:
(Un troisième cas de leucémie à Paris!)
Last update: Mar. 8, 2005
- case 1,
- case 2,
- case 3.
.January 2005, third adverse event in Paris!
Initiated: Jan. 24,
You are welcome to send your
feedback by email to Sandro
stained white cells smear, with leukaemic cells
Bad news strike back a third time....
In 2000 Alain Fischer published his first results on the treatment of young patients suffering from a rare condition due to a single gene defect. The medical team has meanwhile pursued the same type of investigations on 11 patients. 10 therof had beed successfully cured.
By October 2, 2002 the trial has been voluntary suspended by after the team reported a leukemia-like condition emerging in one of the patients. The purpose of this page is to keep interested people constantly informed about the development and the aftermath of this adverse event. The AF team has managed the case with extreme professionality and transparence and reported at the annual meeting of the European society for gene therapy (ESGT, Antibes, 16-20 Oct 2002). The hope at that time was that this ought to be just an erratic phenomenon.
By January 14, 2003, we unfortunately hear that a second case similar to the one reported in October has emerged in the cohort of treated patients. Although the role of insertional mutagenesis as a sole causative agent for these cases remains to be elucidated, the picture is getting somewhat worrysome.
By January 24, 2005, a third case of T-cell hyperproliferatzion is publically disclosed. This page is dedicated to that third case and its consequences and reactions.
Media Box 03:
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Chronology of case 1
Facts and questions after case 1
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Chronology of case 2
Facts and questions after case 2
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Chronology of case 3
Facts and questions after case 3
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3rd complication case in DICS X gene therapy clinical trial
AFSSAPS, http://afssaps.sante.fr/ang/indang.htm, 24 janvier 2005
In May 2004, the French Health Product Safety Agency (Afssaps) authorised the restart of the gene therapy clinical trial conducted by Prof. Alain Fischer and Marina Cavazzana-Calvo, in Necker-Enfants-Malades hospital in Paris. The clinical trial is aimed at assessing efficacy of a gene therapy approach in the treatment of X-linked severe combined Immuno-deficiency (X-SCID), an inherited genetic disease.
This clinical trial, which included 11 patients, was put on hold in October 2002 (see press release October 3rd 2002), after a first notification of a complication in one of the patients had been observed, consisting in an uncontrolled T-lymphocyte proliferation. The same complication has been reported for a second patient at the end of 2002 (see Afssaps Press release dated 15 January 2003). The hold was maintained until analysis and identification of the mechanism(s) responsible. One of the patients died last October, the other is progressively recovering.
The clinical trial has been authorised to resume after the investigators proposed several protocol modifications (number of administrated cells, inclusion criteria, age of the patients to be enrolled, etc. ) aimed at reducing the risk of insertional oncogenesis. Since the restart of the clinical trial, one new patient has been treated. On January 18th, 2005, a new complication was notified to Afssaps. It concerns a third child who was 9 months old when receiving the treatment in April 2002. This complication is also a T-lymphocytes proliferation, which characteristics are still under investigation.
Following this information, and in agreement with Afssaps, the investigators and promoter decided to put on hold the clinical trial again, and wait for further investigations in an attempt to better explain the mechanism of the adverse event.
Contact : Aude Chaboissier, Tél. 01 55 87 30 33, firstname.lastname@example.org
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March 3, 2005
Gene Therapy Is Facing a Crucial Hearing
[The New York Times] http://www.nytimes.com/2005/03/03/politics/03gene.html?pagewanted=print&position=
By GARDINER HARRIS
[W] ASHINGTON, March 2 - Fifteen years after experiments with human gene therapy began in earnest, a federal drug advisory panel on Friday will discuss the death of a French child in one such experiment and why, after so many years of hope, the technology has been such a disappointment.Three major gene therapy trials in the United States have been suspended pending the outcome of the meeting. Dr. Donald Kohn, the principal investigator in one of those trials, said, "I'm going to tell the committee that there is a significant difference between the French trial and ours."
Dr. Kohn, a professor of pediatrics and microbiology at the University of Southern California Keck School of Medicine, said that the type of immune deficiency in his trial's patients was different from that in the French research and that the genes that were made the target of the therapies were therefore also different.
What the Food and Drug Administration wants to know is whether those differences are significant enough, said the advisory committee's chairman, Dr. Mahendra S. Rao, a researcher at the National Institute on Aging. If there is a concern with gene therapy, Dr. Rao said, "is it a general concern, or should it be limited?" The French study was once hailed as one of the first breakthroughs in gene therapy: 10 children suffering from a rare immune disorder were largely cured. But three of those children have since developed leukemia, and one of the three has died.
For years, gene therapy was heralded as a technology that would soon yield blockbuster drug innovations. The National Institutes of Health issued thousands of grants to pursue the research, hundreds of patents have been granted on the technology, and more than 150 biotechnology companies have been created in the last 15 years to exploit it. In 1997 alone, the peak year, 24 such companies were created, said Dr. Sheldon Krimsky, a professor at Tufts University.
Then, in 1999, a teenager, Jesse Gelsinger, died in a gene therapy experiment conducted by researchers at the University of Pennsylvania. The death cast a pall over the entire field, and last month the university agreed to pay the government more than $500,000 to settle fraud allegations related to the case.
Gene therapy's disappointing history is mirrored in other medical technologies once highly promoted, like high-throughput chemical screening and the decoding of the human genome. Reaping the fruits of such technological advances is taking much longer than executives in biotechnology and pharmaceuticals once suggested. As a result, the industries are suffering a drought of new products and are trying to explain why their laboratories have burned through so much money in recent years with so little to show for it.
Many of the companies established since 1990 to pursue gene therapy work have since shifted to other technologies. Cell Genesys, in South San Francisco, Calif., once focused entirely on gene therapy, but in 2001 it spun off much such research into privately held Ceregene, based in San Diego. "We're just a cancer company now," said Ina Cu, a Cell Genesys spokeswoman.
Despite the problems, gene therapy is still routinely heralded as the next big thing, and the field's researchers get a bit defensive when discussing the many problems that have plagued it. But several top researchers agreed in interviews that much of the early optimism had been wrongheaded and that marketable cures were years away. "Still, I would like to think that we can solve these problems," said Dr. Katherine High, a professor of pediatrics at the University of Pennsylvania. Dr. High said she was dismayed that so many biotechnology and pharmaceutical companies had abandoned gene therapy in recent years. "The problem with biotech companies is that they don't have years and years of money," she said. "They need a product within a few years, and the timelines involved in bringing cell and gene therapy to fruition are far too long."
Dr. Kohn, the principal researcher in one of the three trials now suspended, suggested that gene therapy could follow the same path as monoclonal antibodies, which took nearly 30 years to evolve from discovery to marketed therapies. "This is much more of an academic venture than a commercial one at this point," Dr. Kohn said. The lesson of gene therapy, Dr. Krimsky said, is that investors and journalists should react more skeptically to claims of imminent breakthroughs. "It's always that very simple model that brings in a lot of venture capital and the hope of a simple cure around the corner," he said. "People tend to underestimate the complexity of the human body."
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Friday, March 4, 2005; Page A02
Boy's Cancer Prompts FDA to Halt Gene Therapy
By Rick Weiss, Washington Post Staff Writer
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 due 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.
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 having developed cancer from the treatment 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, 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.
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 immunodeficiency, 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 do not 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 to 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 a suspension of all similar experiments. A second treated boy was diagnosed with cancer in December of that year. Both had been treated while infants and developed leukemia about 2 1/2 years later. Although both appeared to respond well to chemotherapy, one of the boys died this past 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 two weeks after the team had begun gene therapy on a new patient, Fischer said in a phone interview. He said he immediately stopped the study again and, although he is not regulated by the FDA, notified the 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 L. Malech and Jennifer Puck at the National Institutes of Health, who have treated two patients so far. The other, led by Donald B. 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 -- along with the other dozen or so children treated previously -- is 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 E. Dunbar of the National Heart, Lung and Blood Institute. But with an average follow-up of about three years so far, it is 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, said Dunbar, who called the fatal cancer "very concerning."
In both the human and monkey gene therapy experiments, the mouse virus used -- known as a murine retrovirus -- is the most common means of delivering DNA. The virus's 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 A. Kay, a professor of pediatrics and genetics at Stanford University and president-elect of the American Society of 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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March 4 2005
Check on gene therapy after leukaemia scare in France
By Roger Highfield, Science Editor
A British gene therapy trial is to be reviewed after three boys developed leukaemia in a similar French trial. One of the boys died. In the French trial, 11 boys received gene therapy for a life-threatening immune disorder, severe combined immunodeficiency (X-SCID), freeing them from the need to live in sterile bubbles. But almost three years after the treatment, white blood cells (called T cells) of the two youngest patients began proliferating abnormally, as they would in the blood cancer leukaemia.
The trial by Prof Alain Fischer, of the Necker-Enfants Malades clinic in Paris, was stopped as a result. One of the children died last year and a third has since developed leukaemia. It marks another setback for gene therapy, which offers hope of new treatments for the 4,000 hereditary diseases caused by a defect in a single gene. The therapy uses a virus as a "vector" to introduce a corrected version of the damaged gene. A similar approach was used to treat boys in Britain by Prof Adrian Thrasher and Dr Bobby Gaspar, of the Institute of Child Health in London, starting with Rhys Evans in 2002.
In the wake of the latest leukaemia, the Gene Therapy Advisory Committee is to carry out a safety review. In Britain, seven children and one adult have been treated so far with gene therapy for X-SCID. None has shown any signs of leukaemia and all are fine. The same approach has also been effective in treating another immune deficiency, called ADA deficiency, in both the institute and in Milan.
A spokesman for the Department of Health said: "Without treatment, babies with X-SCID rarely survive beyond their first birthday. "Until recently, the only cure for X-SCID was a bone marrow transplant but this can only be done using a donor of the same or similar tissue type as the patient. "For children with no donor, gene therapy offers an alternative treatment." The Gene Therapy Advisory Committee and the Committee on Safety of Medicines will meet this month to review all X-SCID studies data. Prof Fischer said yesterday the two surviving boys who developed leukaemia "are doing well, one being now off treatment with the persistent benefit of gene therapy".
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March 4, 2005
Gene Therapy Experiments Put on Hold
Suspension comes as a third child in a French study develops leukemia. Researchers in U.S. believe incidents form an isolated case.
By Thomas H. Maugh II, Times Staff Writer
Federal authorities have temporarily suspended three gene therapy experiments &emdash; two of them in Los Angeles &emdash; 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.
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March 4, 2005
Gene therapy experiments halted after 3rd cancer case
Latest: The Food and Drug Administration (FDA) 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 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.
Setbacks: 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.
Cancer case: The latest cancer case appeared a few weeks ago, in a 3-year-old boy Fischer treated in the summer of 2002 for X-linked severe combined immune deficiency
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Mar. 04, 2005
FDA shuts down three gene therapy experiments; two in Los Angeles
Associated Press mercury News
LOS ANGELES - The Food and Drug Administration shut down three gene therapy experiments, including two in Los Angeles, after health officials learned that a similar French study resulted in the death of a child and another developing leukemia, a newspaper reported Friday.
An FDA panel is scheduled to meet Friday to determine whether the cases abroad are precursors of problems that could arise from current and future experiments, the Los Angeles Times said. The experiments under review involve gene therapy treatments for severe combined immune deficiency, a genetic disorder that leaves victims unable to fight off infections and germs. The disorder is often called the "bubble boy disease," named after a Houston victim, David, who lived for years in a plastic bubble filled with filtered air.
According to the Times, the FDA's move came after Dr. Alain Fischer of the Necker Hospital in Paris recently revealed that his gene therapy experiments led to the deaths of one of two children who had developed leukemia two years ago. A third child treated in Fischer's experiments has developed leukemia, the newspaper said. The FDA, which has not formally announced the move, temporarily shut down three gene therapy experiments for severe combined immune deficiency, including two separate experiments by Dr. Donald Kohn and Dr. Kenneth I. Weinberg of the Keck School of Medicine at the University of Southern California.
Federal officials also halted joint experiments by Dr. Harry L. Malech and Dr. Jennifer Puck of the National Institute of Allergy and Infectious Diseases. Malech and Puck have treated two patients, and Kohn has treated four patients. "Every time we have had patients we want to treat, more (news) comes out of France," said Weinberg, who has not treated a single patient. Phone calls to USC officials seeking comment were not immediately returned early Friday. In addition to Fischer's experiments, federal officials were also alarmed following last month's discovery that gene therapy experiments at the National Heart, Lung and Blood Institute led to 42 monkeys developing cancer.
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Trial of treatment for rare, childhood illness is halted, again.
Nature 433, 561 (10 February 2005); doi:10.1038/433561a
[WASHINGTON] Scientists have halted clinical trials of gene therapy to treat a rare immune disorder &emdash; less than a year after the trials were relaunched following an earlier stoppage.
The trials use gene therapy to treat different forms of severe combined immunodeficiency disease (SCID). The first trial to be stopped was halted in October 2002, and other trials were halted three months later, after two children in the trials developed cancer. But authorities allowed them to resume during the past year because the treatment had cured many children who lack reliable alternative treatments.
Researchers have now halted the trials again, after a third patient was found to have developed cancer. The suspension is a significant setback for the nascent field of gene therapy, because SCID treatment has been its most promising application to date. The child with cancer was a patient of Alain Fischer of the Necker Hospital in Paris. He has been using gene therapy to treat the X-linked form of SCID, which is otherwise only treatable with bone-marrow transplant and is still often fatal. Fischer's trial restarted last May, and his team has treated one child since then.
But on 24 January, the French medical regulatory authority AFSSPS announced that a child who was treated by Fischer in April 2002 now has cancer. As a result, Fischer's trial and similar ones in the United States have been halted again. The agency also said that one of the original two patients who had been diagnosed with cancer &emdash; both of whom were in Fischer's trial &emdash; died last October.
Fischer is now investigating why the third child, who was treated at a later age than the previous two children, developed cancer. The child's cells did not seem to have the same genetic glitch that caused the first two cancers, he says, but he cautions that the analysis is still under way. Fischer adds that he still believes in gene therapy as a treatment for X-linked SCID, because 15 children treated in this way are still alive, and 14 are doing well four years later. But his group will not treat any more children using its current gene-therapy system, he says. He adds that he plans to change a key step in the treatment by changing the vector &emdash; the modified virus that delivers the therapeutic gene to the patients.
"The efficacy is there, but we have to improve on the safety," Fischer says, adding that this is "not an uncommon situation" in medical research.
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Fri, Mar. 04, 2005
Officials recommend limiting gene therapy treatments for children with a severe immune deficiency
PAULINE JELINEK, Associated Press
WASHINGTON - Federal health advisers recommended Friday that gene therapy treatments for children with a severe immune deficiency be restricted to those who have no alternative. The Food and Drug Administration convened the panel after a 3-year-old French boy became the third child to develop cancer after receiving gene therapy for treatment for X-linked severe combined immunodeficiency, or X-SCID. The FDA had asked U.S. researchers doing similar work to put it on hold.
Doctors and scientists on the advisory panel said they didn't want to hold up the therapy for children who have already failed to respond to bone marrow transplants, an alternative treatment. But they noted that the number of such children - who under Friday's recommendation would still be able to have experimental gene therapy - is very small.
"What is happening here today - the big picture - is that it shows the difficulty in developing any new class of therapy," said Dr. Daniel Salomon, professor in the Scripps Research Institute and a member of the FDA panel. "There was a period of time that there was a tendency to say gene therapy ... had been safe. What's clear now is that (problems can develop in) some gene therapy for some diseases," Salomon said.
The panel recommended that gene therapy trials could go forward for a similar ailment called ADA-SCID, finding it is a different issue and no reason to limit those. Ten children suffering with X-SCID were basically cured in the French study, at first greeted with great excitement as a breakthrough in gene therapy, said Dr. Warren Leonard, panel member from the National Institutes of Health. But three later developed leukemia, and one of them died.
"The landscape has changed," Salomon said. He and others said the research needs continued close monitoring but that the setbacks should be kept in context. "The key principle is that all new treatments in medicine go forward through periods where you make a significant advance and you also find that there are setbacks," Salomon said.
The biggest blow to the research field was the 1999 death of teenager Jesse Gelsinger in his fourth day of a gene therapy experiment conducted by researchers at the University of Pennsylvania. Gelsinger, of Tucson, had suffered from an inherited disorder that blocks the body from properly processing nitrogen. Researchers had hoped to cure him by injecting him with a modified virus carrying a gene that could replace the medications and special diet that had been controlling his condition. The Food and Drug Administration concluded that the injection killed him.
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March 4 2005
FDA Panel Recommends Limited Gene Therapy
By Amanda Gardner, HealthDay Reporter
FRIDAY, March 4 (HealthDay News) -- Federal health advisers recommended late Friday that experimental gene therapy treatments for children with a severe immune deficiency continue, but be restricted to those who have no alternative.
The recommendation from a Food and Drug Administration advisory panel came on the heels of a sudden halting of several U.S. gene therapy trials following word that a third child, a 3-year-old French boy, had developed cancer after the therapy, the Associated Press reported. The developments are the latest in a string of problems for gene therapy research, which once held the promise of revolutionizing medicine in its attempt to substitute healthy genes for defective ones.
There have been thousands of attempts to use gene therapy, but only about 10 patients have been cured, all of them children in Europe who were born with the severe immune system disorder called X-linked severe combined immunodeficiency, or X-SCID.
The doctors and scientists on the Cellular, Tissue and Gene Therapies Advisory Committee said Friday that they didn't want to hold up the therapy for children who have already failed to respond to bone marrow transplants, an alternative treatment for X-SCID. But they noted that the number of such children is very small, AP reported. "What is happening here today -- the big picture -- is that it shows the difficulty in developing any new class of therapy," said panel member Dr. Daniel Salomon, a professor in the Scripps Research Institute. "There was a period of time that there was a tendency to say gene therapy ... had been safe. What's clear now is that (problems can develop in) some gene therapy for some diseases," Salomon said.
But even as the panel was meeting, other scientists said they still believe the emerging field has a future in medicine, despite the high-profile setbacks. "Gene therapy's future, in my opinion, is still bright," said Richard Heller, a professor of microbiology and immunology at the University of South Florida College of Medicine in Tampa. "It's still a fairly young field, and genetic manipulation is not easy."
Dr. Theodore Friedmann, director of the Program in Human Gene Therapy at the University of California, San Diego, added, "These are normal problems with a difficult new therapy. The field has obviously been hampered and complicated by some missteps, reversals and, in fact, disasters. But that also comes on the background of hype and exaggeration and failure to deliver very quickly on clinical promises."
The most recent reversal involved a 3-year-old French boy born with X-SCID, the "bubble boy" syndrome, who was just diagnosed with cancer. The boy had undergone gene therapy in 2002. One of the other two children who underwent the therapy in France died in October. In 1999, tragedy also struck when an American teen, Jesse Gelsinger, died while undergoing gene therapy at the University of Pennsylvania. Gelsinger, who was 18, suffered from a rare liver disorder. He died after being injected with special viruses designed to carry healthy copies of a gene into his body.
While acknowledging there have been tragedies, experts in the field also note that one must weigh the risks with the benefits. "These kids with SCID don't have much of a chance," said Fred Modell, co-founder of the Jeffrey Modell Foundation, which represents thousands of patients with immune disorders. "These are children who would not have survived." Modell's son, Jeffrey, died of an immune system disorder in 1986, when he was 15.
Added Friedmann: "At least a handful of participants [in the French trials] with SCID are leading normal lives. These are kids who have an alternative fate and that fate is dying of infection, being isolated and not leading any kind of normal childhood life." "What this study [the French research] shows in principle is that one can correct terrible disease in humans with this sort of approach," he continued. "It also tells us that we're very immature in our technology, that we don't know nearly enough to be pleased with the technology as it is." Friedmann pointed to past successes that started out with mixed results: chemotherapy, organ transplantation, bone marrow transplants.
Dr. Mark Tuszynski, a professor of neurosciences at the University of California, San Diego, who is researching gene therapy in Alzheimer's disease, said, "Whenever one's developing a new technology in medicine, it takes time to work through things. It's naive to think that there would not be wrinkles along the path. But the potential of gene therapy to radically alter how we treat diseases is profound, and I think there remains great enthusiasm in the field in working with gene therapy."
Regarding the children in France, he said, "Those children had no realistic alternative. If this had been a field other than gene therapy this would have been treated as a great success. There's something unfortunate about the perception in gene therapy that should be realistically reassessed so we can recognize that the potential is indeed being realized." One aspect of gene therapy under scrutiny is the "delivery systems" used to get a gene into the human body. The French researchers injected patients with inactivated retroviruses -- viruses that are unable to replicate -- sort of like a missile delivering a payload (the gene).
Retroviruses integrate into the genetic structure of cells, which is really what you need when trying to correct a genetic defect, Heller explained. "The vector specifically is one that sits down in the genome of the host cell and doesn't have a specific targeted site that it goes to," Friedmann explained. This can have unintended consequences, such as the development of cancer down the line, Friedmann said.
Many researchers are now looking into techniques that would better direct where the integration happens. Heller, for instance, is using a nonviral approach, plasmid DNA, as a potential treatment for advanced melanoma. The plasmid DNA, which encodes a gene that stimulates the immune system, is injected directly into the tumor site. An electric field is then applied to help the tumor cells take up the plasmid. Eighty percent of mice with advanced melanoma were cured by this therapy. A trial in humans is under way at the University of South Florida's Moffitt Center, he said. "Right now, the focus is on one vector system, and there are lots of different viruses, as well as nonviral systems, which are showing success," Heller said.
In fact, the FDA panel Friday recommended that gene therapy trials could go forward for another immune ailment called ADA-SCID, saying it was a different issue from X-SCID and therefore there was no reason to limit such trials.
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March 5, 2005
FDA panel recommends caution on gene therapy
By Dennis O'Brien
ROCKVILLE -- A Food and Drug Administration advisory panel recommended yesterday that two gene therapy experiments be allowed to resume only if the patients have exhausted other "reasonable alternatives," including bone marrow transplants. Otherwise, the panel suggested the trials -- at the National Institutes of Health and the University of Southern California -- remain suspended.
Along with another trial at USC, the experiments had been curtailed after a third child developed leukemia in a similar French study. "The additional data hasn't suggested that there's a heightened risk, but we have to be careful," said Dr. Mahendra Rao, chairman of the FDA's Cellular, Tissue and Gene Therapies Advisory Committee.
Rao said the committee scheduled yesterday's session after learning about the third child, who developed cancer while undergoing gene therapy in the French medical trial. Two other children developed leukemia in the French trial in 2002, and one of those children died in October. Great Britain has allowed a study to continue. The FDA has set no schedule for when it may act on the panel's recommendations.
French authorities reported the most recent cancer case Jan. 24, prompting the FDA to suspend the three U.S. gene therapy trials. The action did not pertain to any of the 15 gene therapy studies that are being conducted at the Johns Hopkins School of Medicine and that are focused in different areas.
The experiments being examined by the FDA involve treatment for severe combined immunodeficiency disease, or SCID, a potentially fatal genetic disorder. Victims -- including the "boy in the bubble," who lived 12 years in a sterile enclosure -- are susceptible to lifethreatening infections. The FDA panel recommended yesterday that one of the three suspended trials be allowed to resume because researchers in that trial at USC are treating a variation of SCID that differs from the strain being treated by French researchers. "I'm hoping this will lead the FDA to take our study off hold," said Donald Kohn, a professor of pediatrics and principal investigator for the USC study that the panel recommended be allowed to continue.
Kohn said that he has had no problems in the 18 patients he has treated and that some of them have been undergoing gene therapy for as long as 10 years. In the French study, researchers had successfully treated 17 children with SCID, making it one of the most promising areas of research. But two years ago, Dr. Alain Fischer, a researcher at the Necker Hospital in Paris, reported that two of his patients developed leukemia, prompting the FDA to halt a number of gene therapy trials in the United States. They were later allowed to resume.
Hopes for treatment
Gene therapy was heralded as a major breakthrough when researchers began work in the early 1990s, with hopes that it would lead to cures for a variety of genetic disorders, such as cancer, Parkinson's disease and cystic fibrosis. But the field has seen its share of disappointments. A teenager died while undergoing gene therapy at the University of Pennsylvania. At yesterday's hearing, panel members expressed concerns about future problems in gene therapy trials. "As more data is accumulating, it makes me more nervous, whether we see another case like this or not," said Dr. Bruce R. Blazar, a bone marrow expert at the University of Minnesota.
Panel members said that in many cases, bone marrow transplants have proved to be an effective alternative for children who have SCID and are diagnosed early. "We have SCIDs patients who are in college and some who have graduated, who are doing very well," said Dr. Rebecca Buckley, a professor of pediatrics at Duke University Medical Center.
Buckley said the problem is SCID is associated with several genes, making it difficult to develop one gene therapy that works. "I think we have to think of SCID as 10 different diseases because there are about 10 different genes that when mutated, give you SCID," she said.
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