somatic gene therapy
.
October 2002, Gene Therapy adverse event in Paris

Media Box 01

(Ein Gentherapie-Versuch wurde in Paris unterbrochen)
(Un essai de thérapie génique interrompu a Paris)

Go to MediaBox 02 describing most recent reactions to the second adverse event. Send your feedback to Sandro Rusconi


  • Prof. Alain Fischer
    .
    Hôpital Necker, Paris
    .
    see their homepage

Years of careful clinical investigation ...

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 suspended by French authorities 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.

Unfortunately, by January 14, 2003, we 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 direct causative agent for these cases remains to be elucidated, the picture is getting worrysome.

Comments by SR on second case (19.1.03)
Chronology and Facts (update 15.01.03)
Comments by SR (October 2002)
Description of the research of A.Fischer
.

Media Box 02
reaction from the press and institutions to second adverse event
announced January 14, 2003

Media Box 01
reaction from the press and official institutions to the first adverse event
announced Oct 02, 2002


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European Society of Gene Therapy (ESGT)

Press release, October 25, 2002, For immediate release

For queries contact::

Univ. Prof. Dr. Med. Bernd Gansbacher
ESGT Central Office,
Institut für Experimentelle Onkologie und Therapieforschung,
Technische Universität München
Ismaninger Str. 22
81675 Munich, Germany
Tel: +49-89-41404450
Fax: +49-89-41404476
http://www.esgt.org

Annual meeting of the ESGT:
French gene therapy group reports on the adverse event in a clinical trial
of gene therapy for X-linked severe combined immune deficiency (X-SCID).

Position of the ESGT.

Background

News of a serious adverse event in a clinical trial of gene therapy for inherited, X chromosome-linked Severe Combined Immunodeficiency (X-SCID) were made public on October 2nd, 2002, by the group of French scientists performing the trial, led by Alain Fischer and Marina Cavazzana-Calvo at the Hôpital Necker Enfants Malade in Paris. The investigators announced that one of the patients under treatment had unexpectedly developed a monoclonal lymphoproliferative disease (a leukemia-like disorder), and was receiving chemotherapy. ESGT fully supported the investigators' and French regulatory authority's decision to put the trial on hold pending further investigations (see the ESGT statement posted on October 7th on the ESGT web site at http://www.esgt.org). The French investigators decided to share with the scientific community their data on the adverse event by presenting the case at the ESGT annual meeting held in Antibes (France), October 13-16. Dr. Marina Cavazzana-Calvo delivered the presentation on October 16th to an audience of more than 500 scientists and experts in the field, mainly from Europe and the United States. The presentation, and the discussion that followed, were chaired by Mark Kay, M.D. Ph.D., from the University of Stanford, and Michel Sadelain, M.D. Ph.D., from the Sloan Kettering Cancer Research Center in New York (USA). A transcript of both the presentation and the discussion will be available soon on the ESGT web page at http://www.esgt.org.

The French X-SCID gene therapy trial

Inherited X-SCID is characterized by absence of both B and T cells of the immune system, leading to severe and recurrent infections that are usually fatal in the first years of life. Bone marrow transplantation (BMT) can be a successful treatment option, but it works bests when there is a fully compatible donor. Unfortunately, this is the case for less than one third of X-SCID children. For the others, unmatched BMT carries a high risk of graft failure, graft-versus-host disease, lymphoma, and other medical problems.

The gene therapy trial carried out by Fischer and co-workers involves integration of a therapeutic gene into the X-SCID patients' own bone marrow cells. This approach avoids rejection problems and the need of a compatible donor. Dr. Cavazzana-Calvo reported that gene therapy has achieved effective and life-saving immune reconstitution in 10 out of 11 patients treated so far. All patients are alive and well, and have been able to lead a normal life for periods up to 3 years for the first group of patients. From a clinical point of view, these patients should be considered cured by this pioneering gene therapy treatment.

However, one of the patients developed 30 months after treatment a monoclonal gamma-delta T-cell lymphoproliferative disorder. The investigators promptly recognized early signs of the disease, followed its progression, and eventually decided to start a chemotherapy. The patient responded to the therapy, and is currently under treatment.

The causes of this adverse events have not been conclusively established. As outlined by Dr. Kay in his introduction to Dr. Cavazzana-Calvo's presentation, many factors could have potentially contributed to the origin of the malignant transformation, including malfunction of the therapeutic gene, which encodes a common subunit of various T-cell growth factor receptors, insertion of the gene transfer vector in a cancer-causing gene, genetic predisposition, or other factors causing abnormal expansion, and eventually malignant transformation, of a single T-cell clone. Dr. Cavazzana-Calvo indeed mentioned a history of childhood tumors in the patient's family. She also reported an episode of chickenpox infection in this patient preceding the occurrence of the malignancy. The infection might have caused an abnormal proliferative expansion of immunoreactive T-cells. She also reported that the leukemic cells were positive to a molecular test for the presence of the chickenpox (varicella-zoster) herpes-like virus.

Since the investigators were able to collect cells throughout the progression of the disease, many details on the molecular characteristics of the leukemic cells were discovered, and were communicated to the audience. Dr. Cavazzana-Calvo said that the expression of the therapeutic gene was within the normal range for T-cells, and that its sequence was not mutated in the leukemic clone. Most important, she reported that the leukemic cells carried only one copy of the gene transfer vector that was found integrated in a cell gene normally controlling blood cell proliferation and differentiation. This gene, named LMO2, is abnormally activated in some types of T-cell leukemia, and its expression was indeed elevated in this particular case. Dr. Cavazzana-Calvo speculated that the insertion of the gene transfer vector might have caused this abnormal expression, which in turn might have triggered the leukemic transformation. It seems likely that other events have been required for the development of the malignancy, and, in fact, the majority of leukemic cells were found to carry a chromosomal translocation (t6;13) that was first detectable 34 months after treatment.

The gene transfer vector used in this trial is a retroviral vector, a genetically modified version of a murine retrovirus (an RNA virus). Retroviral vectors insert themselves into the genome of the patient's bone marrow cells. The vector, and the therapeutic gene with it, is then passed on to all the cell progeny, including the immune cells leading to restoration of immune surveillance against infection. It was previously known that wild-type retroviruses can contribute to cancerous changes in a cell they infect if their insertion perturbs a gene involved in regulating normal cell growth and proliferation. This phenomenon is called insertional oncogenesis, and although it was never observed in patients treated with retroviral vectors, it has been accepted as an unlikely but possible risk of gene therapy. In collaboration with Cristof von Kalle at the Institute for Molecular Medicine in Freiburg (Germany), the French scientists were able to determine that the retroviral vector used in this trial was inserted in a specific configuration (an "antisense" orientation) and in a specific region (an intron) of the LMO2 gene on chromosome 11. No abnormal RNA product was observed as a consequence of this event. A more in-depth investigation is necessary to further clarify the cause-effect relationship between the integration event and the malignant transformation, and Dr. Cavazzana-Calvo explained that these tests are being carried out in the laboratory. She also mentioned that the leukemic cells can be grown in culture, and are available to other scientists who might wish to contribute to elucidate the causes of this disease.

During the discussion that followed Dr. Cavazzana-Calvo's presentation, the session chairmen and several investigators in the audience pointed out that insertional oncogenesis was always considered as one of the possible risks associated with the use of retroviral vectors. Although the relationship between the retroviral insertion and the leukemia is admittedly not proven at this stage, the French case shows that what was previously considered as only a theoretical risk of the use of retroviral vectors might eventually be proven as a real one.

Extensive pre-clinical studies of the gene therapy approach used in the X-SCID study had shown no evidence of leukemia or other forms of cancer, and no similar adverse events have been reported in many previous gene therapy trials involving the use of retroviral vectors (see the Journal of Gene Medicine Clinical Trial Database at http://www.wiley.co.uk/genetherapy/clinical/). Claudio Bordignon, from the San Raffaele Institute in Milano (Italy), who this year reported the successful treatment of two patients affected by a similar immunodeficiency (the ADA-deficient SCID) by gene therapy, pointed out that risks could be different for each disease, each therapeutic gene and each class of patients, and that every gene therapy trial involving the use of retroviral, or other integrating vectors should therefore be preceded by a careful assessment of the risk-benefit ratio.

Regulatory consequences

As a consequence of the announcement of the adverse event by the French group, the Food and Drug Administration (FDA) in the US and regulatory authorities in France, Germany and Italy put similar gene therapy trials on hold, pending further investigations on the cause of the malignancy. In Germany and Italy the moratorium went as far as to stop the enrolment of new patients in any clinical trial involving the use of retroviral vectors. Klaus Chichutek, from the Paul-Ehrlich Institute in Langen (Germany), pointed out that the temporary hold on clinical trials operating in Germany is meant to provide the clinicians with the opportunity to reassess their risk-benefit ratios, and to reformulate their informed consents in order to give as much information as possible to the patients and their families.

The general consensus in the audience was that clinical trials should be allowed to resume worldwide as soon as possible, with new guidelines in place for risk assessment and informed consent procedures.

The position of ESGT

Patient safety is the major consideration in early clinical investigative studies, and all possible efforts must be made to minimize the risks for the patients involved. ESGT, as an association of professionals dedicated to the development of gene and cell therapies, encourages and supports the efforts of the investigators to understand the causes of this adverse event, and its broader implications for therapeutic interventions using comparable technology and associated with similar risks. ESGT members are ready to work with European regulatory authorities to thoroughly investigate this particular adverse event, and to evaluate any implications it might have for other gene therapy trials using gene transfer vectors and procedures similar to that used by the French group.

ESGT recognizes the role of the many European ethical committees, review boards and regulatory Authorities in over viewing the development of gene therapy trials in a controlled and unbiased fashion. The current adverse event clearly shows that harmonization of criteria and reviewing procedures among the European states would greatly facilitate the development of common ethical rules, and increase public confidence in the regulatory authorities as well as in the operators in the field. In this regard, Europe should acknowledge the role of the FDA as a major player in governing, stabilizing, and ultimately promoting development of new therapies in the US, and accelerate the establishment of the European Medical Evaluation Agency (EMEA) as its European counterpart. ESGT therefore encourages EMEA to take the lead in acknowledging the need for common guidelines, and promote a better coordination between European regulatory agencies.

ESGT recognizes the need of more pre-clinical investigation in assessing the risk of gene therapy, including more basic research in the development of safer gene transfer vectors. At the same time, ESGT recognizes that there is no real substitute for clinical investigation, and that a correct assessment of the risk/benefit ratio for every patient involved in a clinical trial is the first and most important ethical criterion, for gene therapy as for any other medical treatment.

The position of ESGT is that clinical trials in gene therapy should always follow pre-clinical investigation that fully justifies human experimentation. However, unnecessary delays in applying a potentially effective treatment should be minimized wherever possible, since such delays could prevent demonstration of therapeutic potential, postpone development of effective therapeutic products, and ultimately affect the right of patients to have access to an effective treatment in due time.


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Adverse event the clinical trial of gene therapy for the X-linked severe combined immune deficiency disease (XSCID):

Statement by the European Society of Gene Therapy

A serious adverse event has been reported in a clinical trial of gene therapy for inherited, X chromosomelinked Severe Combined Immunodeficiency (XSCID). This trial is being performed by Alain Fischer and Marina Cavazzana-Calvo and their colleagues at the Hôpital Necker Enfants Malade, Paris, France. Inherited XSCID leads to severe and recurrent infection, and is usually fatal in the first years of life. Bone marrow transplantation (BMT) is a possible therapy for XSCID. However, the majority of patients lack a matched donor, and BMT is associated to significant risks including graft-versus-host disease, incomplete immune reconstitution, rejection of the graft and lymphoma. Investigations of new treatments such as gene therapy are crucially required to improve the survival chances and quality of life of these patients. The Fischer gene therapy trial involves integration of a therapeutic gene into the bone marrow cells of XSCID patients followed by re-transplantation. This approach avoids rejection problems and has achieved effective life-saving immune reconstitution in 8 out of 9 patients treated to date, most of whom have been able so far to lead a normal life for periods now of up to 3 years.

However, one of the patients has unexpectedly developed a monoclonal lymphoproliferative disease and is receiving chemotherapy. The cause of this leukaemia, and whether it is related to the gene therapy procedure, is not yet known. Therefore, ESGT fully supports the investigators' and French regulatory authority's decision to put the trial on hold pending further investigations.

Patient safety is the major consideration in early clinical investigative studies of this nature, and ESGT members are ready to work with European regulatory authorities to thoroughly investigate this adverse event, and to evaluate any implications for other gene therapy trials using gene transfer vectors and procedures similar to that used by the French group. Retroviral vectors of the type used in the trial insert genes into the chromosomes of patient bone marrow cells. The curative gene is then passed on to all the cells of the blood system, including the immune cells, leading to restoration of immune surveillance against infection. Retroviruses in the wild can contribute to cancerous changes in a cell if they perturb another gene involved in regulating normal growth. This phenomenon is called insertional oncogenesis, and although it was never observed in patients treated with retroviral vectors, it has been accepted as an unlikely but possible risk of gene therapy. As suggested by the French investigators, there is thus a possibility that the monoclonal lymphoproliferation observed in the XSCID patient was caused by insertional oncogenesis.

Patients, their families and the clinical professionals are aware of the small risk of cancer as an adverse sideeffect of this type of gene therapy. As always in clinical medicine, the risks associated to a new and experimental treatment must be balanced by the potential benefits of the treatment. Extensive pre-clinical studies of the gene therapy approach used in the XSCID study had shown no evidence of leukaemia or other forms of cancer, and no similar adverse events have been reported in previous similar gene therapy trials. In this particular gene therapy trial, however, the success has been much higher and the study more detailed. Dr Fischer, Dr Cavazzana-Calvo and a number of other independent experts are working to try to identify the cause of monoclonal lymphoproliferative disease in this one patient, and to determine whether the retroviral gene therapy procedure has contributed to any special predisposition or risk of leukaemia. Should this proves to be the case, it will be necessary to weigh the frequency of clinical risk versus clinical beneficial of the gene therapy against that of other methods of treatment. The European Society of Gene Therapy, as an association of professionals dedicated to the development of gene and cell therapies, encourages and supports the efforts of the investigators to understand the causes of this adverse event, and its broader implications for therapeutic interventions using comparable technology and associated to similar risks. Current understanding and further details of the case will be presented to the scientific community during the ESGT annual meeting to be held in Antibes (France) on October 13th to 16th. An updated statement including new elements discussed at the Antibes meeting will be released thereafter.

Contact: Professor J George Dickson Secretary of the European Society of Gene Therapy Direct Tel: 44-(0)1784-443545 Secretary Tel: 44-(0)1784-443559 Fax: 44-(0)1784-434326 Email: g.dickson@rhul.ac.uk


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Fantastische Heilung, ohne Gewaehr Daempfer fuer die Gentherapie: Ein behandeltes Kind erkrankte an einer Leukaemie.

NZZ am Sonntag, 20.10.2002, Von Matthias Meili

Der Referatstitel sagt schon alles: 'Gentherapie zwischen Illusion und Realitaet'. So nannte Sandro Rusconi, Professor fuer Biochemie an der Uni Freiburg i. Ue, und einer der engagiertesten Fuersprecher der somatischen Gentherapie in der Schweiz, einen Ueberblicksartikel, den er vor einem Jahr ins Internet (www.unifr.ch/nfp37) einspeiste. In einer Illustration veranschaulicht Rusconi die (Miss-)Erfolgsgeschichte der Gentherapie: eine zwar staendig aufwaerts strebende Kurve, die aber immer wieder abrupt und tief absackt.

Ein solcher Rueckschlag hat sich nun wieder ereignet, und zwar ausgerechnet bei einem Versuch, der bis anhin als Erfolg verbucht worden ist. Ein vom Pariser Kinderarzt Alain Fischer im HÙpital Necker gentherapeutisch behandeltes Kind erkrankte in diesem Fruehjahr an einer Art Blutkrebs - oftenbar als Folge der gentherapeutischen Behandlung. Die franzoesischen Behoerden haben den Versuch gestoppt. Ebenso wurden in den USA drei aehnliche klinische Experimente unterbrochen, und auch die deutschen Kontrollorgane haben angeordnet, einen in Frankfurt lautenden Versuch im Lichte der Pariser Ereignisse zu reevaluieren.

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text truncated for copy-right reasons, please read the full text at: http://nzz.gbi.de/NZZ.ein

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Resumption of Gene Therapy Urged Advisory Panel Backs Restrictions After Treatment Triggered French Boy's Illness

By Rick Weiss Washington Post Staff Writer Friday, October 11, 2002; Page A17

New tests offer overwhelming evidence that a leukemia-like disease diagnosed in a 3-year-old boy in France was triggered by the experimental gene therapy he received as a baby, the first proof that the nascent and troubled field of medicine can cause cancer. Nonetheless, because of the treatment's track record of having apparently cured several children and because the risk of cancer so far appears to be modest, a federal advisory committee yesterday recommended that the Food and Drug Administration reverse its recent suspension of such studies and allow them to continue with new restrictions and protections in place.

"All of us are scared about it and are aware that this has implications," said Daniel R. Salomon, chairman of the FDA's Biological Response Modifiers Advisory Committee, which met in an emergency session yesterday at a hotel in Gaithersburg. "However, one adverse event, serious as it is in the context of the whole field, . . . is not enough to advise the FDA to put all these programs on hold."

The FDA in September halted the three U.S. gene therapy studies that most closely resembled the French experiment, including one that had already treated four children and two that had not yet recruited volunteers. The studies involve infusions of engineered retroviruses to deliver healthy genes into patients with life-threatening immune system deficiencies. Yesterday's meeting was to help the FDA decide whether to reverse, continue or expand that clinical hold. In public testimony before the advisory committee, some called for a full-blown moratorium on gene therapy while others, including relatives of patients, begged the FDA to allow studies to go forward.

The panel's recommendations give a partial reprieve to a field of experimental medicine that has been plagued by failure for a dozen years and that came under extreme criticism after Arizona teen Jesse Gelsinger died in a 1999 experiment. At the same time, however, the latest crisis brought to light the little-noticed fact that, eight years after Congress first urged the FDA to create a registry of all gene therapy participants, the agency has yet to do so. That is complicating efforts, now underway, to get in touch with volunteers who may be at increased risk of cancer from their gene treatments.

"FDA currently has no system in place to locate all patients who were enrolled in clinical trials involving retroviruses," wrote Sen. Richard J. Durbin (D-Ill.) in an angry letter sent to Lester M. Crawford, FDA deputy commissioner, yesterday morning. Durbin first encouraged the FDA to create such a database in 1994 and 1995, and renewed his push after Gelsinger's death. The agency is working to create such a roster, said Philip D. Noguchi, acting director of the FDA office that regulates gene therapy. But Noguchi conceded that without that system in place, the agency has not been able to determine the number of FDA-approved gene therapy studies that have used retroviruses or the number of patients involved in those studies. He estimated that about half of the approximately 300 gene therapy experiments approved by the FDA since 1990 have involved retroviruses for a variety of diseases.

Retroviruses have been popular in gene therapy studies because they can efficiently inject therapeutic genes into patients' cells. But scientists have also long known that in theory, at least, they can also disrupt patients' normal genes, prompting cells to become cancerous. That's apparently what happened to the boy in France. Christof von Kalle, a University of Cincinnati scientist, examined blood cells from the boy, who was born with X-linked severe combined immune deficiency (SCID). He showed the committee how a retrovirus had delivered its therapeutic payload directly into a gene called LMO2 in one of the boy's blood cells. The gene plays a role in cell division and, when disrupted, can lead to blood cancer.

The evidence that the treatment helped trigger the cancer is definitive, Noguchi said. "What we see is that it surely is not a coincidence." At least one additional trigger -- perhaps the bout of chicken pox suffered by the boy just before he was diagnosed with his leukemia syndrome -- probably built on the initial gene injury and ultimately caused the cancer. The boy's sister and another relative also have had cancer, a pattern that complicates the job of measuring the risk of the therapy itself. And it's difficult to weigh the risk of therapeutic alternatives. Bone marrow transplants are almost always curative in the small fraction of SCID cases in which a perfectly matched donor is available, but transplants fail 25 percent to 50 percent of the time when matched donors are not available. Only patients without access to matched marrow are eligible for gene therapy.

Unable to measure those risks accurately and inspired by gene therapy's ongoing potential, the FDA panel recommended that all past and future participants in gene therapy tests involving retroviruses be informed of the new evidence of added risk. The panel also recommended that blood specimens from participants be checked periodically for early evidence of cancer. Alain Fischer, who led the French study at the Necker Hospital in Paris, yesterday said that chemotherapy has reduced the boy's white blood cell levels back to normal, and the team is now considering how to follow up that treatment. He did not give a prognosis for the boy. Paul Gelsinger, Jesse's father, offered FDA officials poignant advice as they prepared to craft specific language for the newly agreed-upon protections: "Imagine these children as your own," he said.


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Gene Therapy Trials May Restart

FDA Advisers Recommend That Gene Therapy Trials Go Forward for Bubble Boy Disease

The Associated Press

GAITHERSBURG, Md. Oct. 11 &emdash; Gene therapy that seems to cure an often fatal immune disorder also likely gave a French toddler a leukemia-like illness, but U.S. scientists want the genetic experiments restarted anyway calling the risk too low to deprive desperate children of treatment. The Food and Drug Administration called an emergency meeting of its scientific advisers Thursday to decide whether three U.S. gene therapy experiments recently suspended because of the French boy's illness should resume. France also suspended the experiment.

The disorder often known as "bubble boy disease" formally called severe combined immunodeficiency, or SCID is the only disease where gene therapy has ever worked. The toddler is the first recipient of gene therapy for any disease to suffer a cancerous side effect. But scientists have long warned that cancer is a possible risk if the virus used to deliver new genes into a patient's body slips into the wrong place.

The evidence "is pretty convincing" that now that has happened, said Dr. Philip Noguchi of the Food and Drug Administration, after French researchers showed evidence the virus they used affected a cancer-promoting gene in the boy's body more than a year after it cured his SCID. It took another year and a half before the boy developed leukemia-like symptoms. Chemotherapy appears to be working, and tests soon should tell if the 3-year-old is in remission, Paris' Dr. Alain Fischer told the FDA meeting.

Still, there is only one report of gene therapy-linked leukemia while some popular chemotherapies carry a 10 percent risk that in curing today's cancer the patient will get leukemia years later, cautioned Dr. Crystal Mackall of the National Cancer Institute. "You can be doing harm when you withhold a promising treatment," added Dr. Joanne Kurtzberg of Duke University, echoing a woman who told the panel that the experiment is her 10-year-old grandson's last hope.

The FDA advisers ultimately recommended that gene therapy experiments be reopened to SCID patients who don't have the option of a bone marrow transplant from a well-matched donor, today's best treatment. The FDA usually follows its advisers' recommendations. But some panelists worried that the leukemia finding's implications go beyond SCID to every gene therapy experiment that ever used a retrovirus, a kind of virus that permanently invades cells.

"We owe an extra measure of regard to all the people still alive who volunteered for gene therapy. They should be told about this risk and check for it," said Abby Meyers of the National Organization for Rare Disorders. She angrily noted that eight years after Congress ordered the FDA to create a registry of gene recipients in case long-term side affects ever appear, the agency hasn't done so. The FDA still is working to ensure survivors of all 150 retroviral gene therapy studies ever done are notified of the French case, Noguchi said.

People signing up for future retroviral gene therapy for any disease must be more strongly warned that leukemia is a risk with specific discussion of the French case, the advisers added. Babies with SCID are born without the ability to produce disease-fighting immune cells. The best known victim was David, Houston's famous "bubble boy" who lived in a germ-proof enclosure until his death at age 12 in 1984.

There are some SCID treatments, including bone marrow transplants that can allow patients to live normal lives. But transplant success varies widely, and many children still die young. So Fischer generated great excitement when his gene therapy apparently cured nine of the 11 children he treated, all with the most severe type of SCID-type, called X-SCID, that afflicts only boys. Similar U.S. studies poised to begin have been put on hold.

Fischer took bone marrow from the boys and culled from it skin cells that are supposed to create blood cells. He mixed in a retrovirus containing the immune-creating gene their bodies lacked, and reinjected the stem cells, which in nine boys started working properly. Intricate molecular studies of the toddler who got the leukemia-like illness three years after his gene therapy found the virus that delivered the SCID-curing gene also inserted itself into numerous other spots on cells, including a leukemia-promoting gene. That alone likely wasn't enough to sicken him, several scientists said, but may have been the final piece of bad luck on top of a family predisposition to cancer and other still unknown factors.


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Gene therapy benefit said to outweigh risk

By Steve Mitchell UPI Medical Correspondent From the Science & Technology Desk Published 10/10/2002 6:43 PM View printer-friendly version

WASHINGTON, Oct. 10 (UPI) -- The benefits of gene therapy far outweigh its risks and such procedures hold the greatest hope for treating currently incurable diseases, experts told United Press International. This assessment was given despite the U.S. Food and Drug Administration's decision to hold an emergency meeting Thursday to examine gene therapy safety issues following the report last week that a person had developed cancer from the treatment.

In addition, a clinical trial of gene therapy in France being conducted at the Hôpital Necker Enfants Malade in Paris was halted after a patient developed leukemia apparently due to the vector that was used to deliver the gene into the body. The trial was using gene therapy to treat patients with X-linked severe combined immune deficiency, a disease that is fatal within the first few years of life if not treated. The FDA acted last week to halt all similar trials in the United States -- there were thought to be only three.Yet these events have no bearing on other gene therapy trials, experts said.

"People tend to group gene therapy together ... but in fact the only similarity is that you're putting a gene in," said Mike Kaplitt, a neurosurgeon at Weill Cornell Medical College in New York City who will soon begin the first ever gene therapy trial for treating Parkinson's disease. "That's like saying every drug therapy is the same because you're putting a drug in." Kaplitt told UPI the problem in the French trial appears to be due to the vector -- usually a virus -- that was used. But he noted different gene therapies use different vectors and not all of them carry this risk. The French trial used a retrovirus that has long been considered to be safe, said French Anderson, director of gene therapy laboratories at the University of Southern California in Los Angeles and the first to use the vector in humans in the early 1990s. Anderson said the vector has been used for 12 years and in more than 3,000 patients before a side effect was seen. It was known the vector had the potential to insert into chromosomes and cause cancer and patients in the French trial were informed of this risk, but it never had occurred until last week, he said.Because it was a known risk, "it's not going to have that much of an impact on the field," Anderson said. Referring to Jesse Gelsinger, who died in 1999 after being treated with gene therapy for a rare metabolic disorder, he said "that was totally unexpected and unexplained and that did have an impact on the field." The vector used in this case was different from that used in the French trial.

The Gelsinger incident resulted in regulatory agencies taking a closer look at gene therapy trials and instituting new safety measures, Anderson said. "The public should have a certain amount of confidence that regulatory agencies around the world are so alert to gene therapy that when one patient in Europe has a problem the whole world knows it within days. The time to get frightened is when you don't know what is happening, when things are kept secret," he said. "In the midst of all this, the public shouldn't lose sight of the potential of these therapies," said Savio Woo, past-president of the American Society of Gene Therapy and director of the gene therapy institute at Mount Sinai University in New York.

"This adverse event needs to be put into context," Woo said. "These type of events (in gene therapy trials) make the front page but out of the thousands of patients who have undergone gene therapy ... the frequency has been really low, certainly no higher than new drugs under development," he said."That's not to say this event is not bad," he added. The scientific community "wants to take this on, find out how it occurred and how to prevent it in the future" because the treatment is "nothing short of spectacular" for patients with SCID, Woo said. He added that 11 of the patients, who would not even survive without treatment, have been given this therapy and 10 are cured and now living normal lives. "If that's not miraculous medicine, I don't know what is," he said.

Anderson agreed, saying, "Gene therapy is the greatest hope people have for what is presently incurable diseases." Kaplitt said the vector he will be using in the Parkinson's trial is largely deemed to be one of the safest. It is called adeno-associated virus, or AAV, and it "has never been associated with any human disease whereas some of the other vectors have been," Kaplitt said. Anderson agreed AAV appears to be safe but he noted that could change. "AAV is thought to be the safest viral vector and that will be the case until they produce a serious adverse event," he said. "It's only a matter of time before something pops up with AAV," he said, noting that it took more than a decade before a side effect was seen with the retrovirus vector used in the French trial. Woo said the risk of such side effects must be taken in the context that gene therapy has enormous potential to cure disease. "There won't be any new medical therapies forever in the future if the public expects a new therapy to be completely safe the first time," he said.Anderson also voiced his support for continuing gene therapy. "Everybody from Paul Gelsinger (Jesse's father) on down have made clear that if these cases were to hamper the progress of gene therapy that would be the biggest tragedy that could happen," he said.


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Paris (ats/afp) Suspension d'un essai de thérapie génique en France

Un essai clinique de thérapie génique a ét interrompu par précaution dans un hôpital de Paris. L'un des enfants traités a développé une maladie "similaire à la leucémie", ont annoncé jeudi les autorités sanitaires françaises. "Chez un de ces patients de cet essai clinique, une complication a été observée. Il s'agit d'une prolifération non contrôlée de lymphocytes qui nécessite actuellement un traitement", a indiqu l'Agence française de sécurité sanitaire des produits de Santé dans un communiqué. L'essai était mené à l'hôpital Necker-Enfants malades de Paris. "Dès la mise en évidence de cette complication, les familles des autres enfants inclus dans cet essai, et la communauté scientifique ont été informées. Les autres enfants sont en bonne santé", souligne l'Agence.

Succès précédents
En avril 2000, une équipe de médecins français avait pour la première fois réussi à corriger grâce à une thérapie génique une grave insuffisance immunitaire héréditaire obligeant des bébés à vivre dans une "bulle" stérile pour éviter les microbes. Ces résultats avaient été confirmés par le succès du traitement de huit patients. La thérapie génique permet de reconstituer le stock de globules blancs, des lymphocytes T et d'autres cellules de défense de l'organisme. Le "déficit immunitaire combiné sévère" (DICS X1) lié au chromosome X, maladie héréditaire rare (cinq cas par an en France), ne frappe que les garçons. Caractérisée par l'absence totale de cellules de défense, elle laisse le malade à la merci de la moindre infection, provoquant sa mort en l'absence de greffe de moelle osseuse ou de l'abri en chambre stérile.

Développement Paris (ats/afp)

Les Etats-Unis suspendent à leur tour les thérapies géniques
Washington (ats/afp) Les autorités sanitaires américaines ont suspendu tous les programmes de thérapie génique contre le déficit immunitaire mortel, selon la presse américaine de vendredi. Cette décision a été prise après le décès (see ********) d'un jeune Français ayant participé à un tel programme. Quatre programmes ont été suspendus aux Etats-Unis, suite à l'annonce jeudi par les autorités sanitaires françaises de l'arrÍt officiel de l'essai, selon le "New York Times", qui cite des responsables de l'agence fédérale pour la sécurité alimentaire et pharmaceutique (FDA). "Ce n'est pas absolument définitif, mais les premières données que nous avons nous amènent à penser que ce n'est sûrement pas une coÔncidence", a déclaré Philip Noguchi, en charge de la recherche en thérapie génique à la FDA. "C'est une expérience qui fait réfléchir, mais nous faisons le nécessaire", a-t-il ajouté.

******************

Contacted by the NFP37, the ATS has issued this correction on October 9th:

09-OCT-2002, RECTIFICATIF - ETRANGER - bsf093 du 4 octobre 2002

La dépêche "Les Etats-Unis suspendent à leur tour les thérapies géniques" diffusée le 4 octobre contenait une erreur dans le lead.
La décision américaine a été prise après qu'un jeune Français ayant participé à un tel programme eut développé une maladie proche du
cancer du sang. Et non comme écrit "après le décès d'un jeune Français".

*****************

Améliorer l'encadrement
Une réunion d'urgence de la FDA est prévue la semaine prochaine à Bethesda, dans l'Etat du Maryland, afin que les scientifiques impliqués dans cette recherche analysent ces dernières données, précise le "Washington Post". Un renforcement de l'encadrement des autres recherches en thérapie génique pourrait Ítre décidé. Au total, onze enfants, de cinq pays différents, ont participé à ce programme de thérapie génique. L'essai est considéré comme le premier et seul traitement génique efficace permettant à des "bébés-bulle" de sortir de leur isolement. Le principe de la thérapie génique expérimentée à l'hôpital Necker, à Paris, consiste à ajouter aux cellules de la moelle osseuse une copie normale d'un gène, le "gamma-c", défectueux chez ces enfants. Ce transfert de gène s'effectue à partir d'un prélèvement de cellules de la moelle du patient.

Rétrovirus de souris
Pour amener le gène sans défaut sur son site de fonctionnement, les médecins ont recours à un rétrovirus de souris utilisé comme véhicule-transporteur. Prélevé sur des souris, il est artificiellement rendu incapable de se reproduire chez les patients. Malgré ces précautions, ce rétrovirus est responsable de la prolifération observée chez le petit malade. Comme prévu, le rétrovirus ne s'est pas reproduit. Mais il a provoqué la "dérégulation" d'un gène voisin qui s'est révélé être un gène de cancer.

NOTE: la dépÍche est complètement remaniée.


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Nouvelliste, 05.10.2002: Thérapies Géniques - Programmes suspendus

Les autorités sanitaires américaines ont suspendu tous les programmes de thérapie génique contre le déficit immunitaire mortel, selon la presse américaine de vendredi. Cette décision a été prise après le décès (*???) d'un jeune Français ayant participé à un tel programme. Quatre programmes ont été suspendus aux Etats-Unis, suite à l'annonce jeudi par les autorités sanitaires françaises de l'arrêt officiel de l'essai, selon le New York Times, qui cite des responsables de l'agence fédérale pour la sécurité alimentaire et pharmaceutique (FDA). Au total, onze enfants, de cinq pays différents, ont participé à ce programme de thérapie génique. L'essai est considéré comme le premier et seul traitement génique efficace permettant à des ´bébés-bulleª de sortir de leur isolement. ATS/AFP

*??? voir dépêche ATS.la légende urbaine se propage...


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Independent news.co.uk: Biotechnology: They promised magic cures, but success is an illusion

By Leo Lewis, 06 October 2002

If the completion of the Human Genome represented the peak of biotechnology excitement, last week represented a dismal trough. Biotech is a science on the cutting edge and well used to painful setbacks, but the double blow suffered over the past five days will take a lot to recover from. The new problems &endash; centred on two health scares arising from biotech-derived treatments &endash; come at a time when, globally, the industry is fighting a rearguard action for survival. Money for research is running down, the demand for bigger and better computers is rising, and, most crucially, the actual business of turning theory into drugs is proving far longer and more troublesome than anyone expected.

The issue of failing to meet expectations is a complex one. Over the past decade, the biotech industry has spoken so convincingly about the potential unleashed by cracking the genetic code that it has created a giant appetite for success with both investors and the general public. Now the industry is being forced into the quiet admission that the miracles are going to take some time, and share prices everywhere have plunged in response.

A breakthrough that might have rescued biotech's reputation last week will probably be added to the industry back-burner. The announcement that scientists had mapped the genetic code of malaria-bearing mosquitoes was combined with the prediction that a cure for the disease is around the corner. More sober analysis suggests a much longer time frame. Last week's news from France had an even more undermining effect. Biotech scientists have spent years working on a gene-based therapy to cure the fatal "bubble baby" syndrome of children born without immune systems. Just when it appeared that the gene therapy had produced the "miracle" cure all had hoped for, French doctors discovered that one child patient had gone on to develop leukaemia.

Although British doctors have vowed to continue with gene therapy trials, French authorities have halted their work on the project. Further testing may bring up explanations for the development, but the issue casts a huge shadow over gene therapies. It has reminded the world in general that gene maps have not yet created a "new paradigm" for drug discovery.

French doctors were also responsible for exposing an even more significant setback for the biotech industry. After four years of research, Nicole Casadevall has cast doubts on Eprex, a protein-based kidney treatment that is the best-selling genetically engineered drug in the history of medicine. Eprex itself is the star product of the US drugs giant Johnson & Johnson, bringing in annual sales of $3.4bn (£2.3bn). More critically, it is the leading product in a whole class of drugs developed over the past decade whose total annual value is more than $13bn. Other drugs makers using the technology include the biotech giant Amgen and the Swiss titan Roche.

The French allegation &endash; that the protein leads to a damaging blood condition called "aplasia" &endash; has cast a big cloud not just over this class of drugs, but over a long-standing cornerstone of biotechnology. The whole technology by which the drug was produced now looks challenged, which could draw in many more drugs produced by other companies. Particularly shocking is the length of time this has taken to emerge &endash; suggesting that other biotech treatments deemed safe may in fact be ticking time-bombs. The incident has produced the predictable response from the biotech researchers, who point to the pitfalls of any new science.

The biotech industry will certainly suffer from these two blows, but the long-term victims may be the drug companies. As many analysts are now concluding, traditional drugs companies were among the biggest believers in the potential of biotech. They allowed its promises to divert them from the traditional approaches to drug discovery, and are now paying the price with meagre pipelines.


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Frankfurter Allgemeine Sonntagszeitung 5.10.02: Wenn Heilung den Tod bringen kann / Von Volker Stollorz

Von Geburt an war Mirko* (*changed name) dem Tod sehr nahe. Dann kam die Heilung. Und jetzt droht Mirko wieder der Tod. Ausgerechnet durch seine Heilung. Das Schicksal des dreijährigen Jungen klingt wie ein Martyrium. Als er zur Welt kam, fehlte ihm jede Immunabwehr. "Schweres kombiniertes Immunschwäche-Syndrom" (Scid-X) lautete die Diagnose. Ein defektes Gen im Erbgut blockiert bei dieser Krankheit die Reifung aller Immunzellen. Der Körper ist Krankheitserregern schutzlos ausgeliefert. Überleben können Kinder wie Mirko nur im Isolierzelt, jede banale Infektion kann tödlich enden. Als Ausweg gilt allein eine Knochenmarktransplantation. Doch bis zu einem Viertel der Kinder überleben den Eingriff nicht ....

Read the rest of this article at: http://www.faz.net/IN/INtemplates/faznet/default.asp?tpl=faz/content.asp&arttype=IH&doc={D960869D-8093-4AA5-87CB-7A3145ED3989}&rub={2A936BB1-8BB4-4BBA-8134-C9AD285C8C81}


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StraitsTimes, October 7, 2002,

US and France halt gene therapy trials: Hitch occurs after French 'bubble' boy undergoing treatment contracts leukaemia-like disease

PARIS - Pioneering gene therapy for so-called 'bubble' patients with no working immune system has hit a setback.

France and the United States halted trials on Thursday after a boy patient contracted a leukaemia-like disease. Researchers announced the French child's illness and suspended the therapy trials, but insisted that the hitch, although serious, did not apply to other trials using gene therapy.

The US Food and Drug Administration suspended certain gene-therapy trials promptly after hearing the news, but Britain's Department of Health said two such trials there would continue despite the risk. 'A complication was detected with one of the patients at the clinic, consisting of an uncontrolled lympho-proliferation which had to be treated,' said the French national health agency. It said the disease was similar to leukaemia, and that the boy had been treated with chemotherapy.

Professor Alain Fischer, who had been conducting the trials at the Necker-Enfants Malades hospital, told a news conference the problem applied only to the therapy for immuno-deficiency, which leaves patients with no defences against disease. They usually live out their short lives in sterile plastic 'bubbles' because any infection would kill them. A total of eight children at the hospital had received gene-therapy treatment for the 'bubble-boy disease'. The other seven were in good health, said the health agency.

Researchers in the US reacted to the news by saying they were not sure whether the treatment had caused the disease in the boy, but that they were stopping trials until they knew more about what had happened. 'The clinical halt is the only ethical course of action until we have the answers,' said Dr Donald Kohn, president-elect of the American Society of Gene Therapy. The British government's Gene Therapy Advisory Service Committee said it was not considering stopping two studies taking place at London's Great Ormond Street hospital.

Gene-therapy research had been recovering from the shock death of an 18-year-old in the US in 1999 after he underwent treatment to have a rare, inherited liver defect corrected. Prof Fischer said other factors besides the gene therapy, such as the fact that he had suffered from chickenpox, could be responsible for the boy's illness. The children in the trials have human severe combined immuno-deficiency (Scid) XI, which leaves them without any working immune system. It only affects boys because it is the X chromosome that is faulty. Girls have an extra X chromosome that can make up the deficiency. In early 2000, the Necker Hospital's Prof Fischer and some colleagues said they had virtually cured two boys with Scid by restoring their immune systems using gene therapy.


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New York Times, 4.10.02 WASHINGTON, Oct. 3

Officials in the United States and France said today that they had suspended four gene therapy experiments
because the treatment, which cured a 3-year-old boy of a fatal immune deficiency, may have given him an illness similar to leukemia.

Scientists conducting the research said it was not clear whether the boy, who was treated as an infant in France, was made sick by the therapy. But officials at the Food and Drug Administration said they suspected that the experiment, which until now had been hailed as the only unequivocal gene therapy success, was responsible."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," said Dr. Philip Noguchi, the agency official who oversees gene therapy research. "It's a sobering experience, but we are doing what should be done."

The experiments - one in France, three in the United States- were suspended in early September. But the news was not made public until today, authorities said, to give the researchers time to notify the families of 14 children enrolled in the trials.The move is yet another major setback for the fledgling field of gene therapy, which involves using viruses to introduce healthy genes into cells. The field is still reeling from the death of Jesse Gelsinger, 18, who lost his life three years ago while undergoing gene therapy at the University of Pennsylvania.

Scientists have long theorized that retroviruses, which were used in the suspended experiments, could trigger cancer. The risk was that the virus, which integrates itself into the patient's DNA, would lodge in or near a cancer-causing gene.But researchers said they had never seen this before, either in animals or humans, even though hundreds of people have received retroviruses in gene therapy experiments for a number of diseases. Experts said it was too soon to tell whether other children treated for immune deficiency were at risk.

"This has been a spectacularly successful endeavor up to this point," said Dr. Savio Woo, former president of the American Society of Gene Therapy. "This is a new enemy that we have discovered. We know that there is a theoretical possibility, but it has never been seen before."The suspended trials sought to cure severe combined immune deficiency, a disorder that leaves infants without working immune systems. Abbreviated as SCID, but commonly called "bubble boy disease," it is extremely rare and is fatal in the first year of life if left untreated.

In the most severe form, the disease affects boys who have faulty X-chromosomes. The only treatment is bone marrow transplant. But the transplants fail in as many as 40 percent of all children who lack a perfect donor match, so scientists looked to gene therapy as an alternative.In April 2000, Dr. Alain Fischer and his colleagues at the Necker children's hospital in Paris announced that they had used gene therapy to successfully insert corrective genes into the bone marrow stem cells of three babies with X-linked SCID. Coming on the heels of Mr. Gelsinger's death, Dr. Fischer's study was hailed as long-sought proof that gene therapy could work.

Dr. Fischer went on to treat six more babies and a teenager, who survived because he had a partial immune deficiency. "Up until now, all these patients, more than three and a half years after treatment, are doing well," he said. All had "close to normal immune functions," he said.But last spring, Dr. Fischer said, one of the boys showed elevated levels of a particular type of white blood cell, known as a T-lymphocyte, though he had no symptoms. Subsequently, though, the boy developed chickenpox. By August, Dr. Fischer said, he had a "significant increase" in the white cell counts, as well as an enlarged spleen, anemia and a drop in platelets.

When scientists examined the child's cells, Dr. Fischer said, they could see that the genetic material of the retrovirus had inserted into a particular gene on the 11th chromosome that controls the proliferation of cells. But he said he was not yet convinced the gene therapy was entirely to blame.Other factors, including the chickenpox infection and a family history of cancer, could also be at work, Dr. Fischer said. 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, said the gene therapy was likely responsible.

"We knew it would happen sooner or later," he said. But even if it turns out that gene therapy causes the disease, Dr. Anderson and other experts said gene therapy might still be used to treat SCID because the illness was so devastating. The child does not have leukemia per se, Dr. Fischer said. There is no name for his proliferation of cells because scientists have never seen it before, so Dr. Fischer is calling it "lymphoproliferation." The boy is being treated with chemotherapy and is responding, Dr. Fischer said. But the abnormal cells have not disappeared, he said. Dr. Fischer said he notified French authorities, as well as the F.D.A. and his colleagues in the field, right after Labor Day, as soon as he knew the problem was serious.

The food and drug agency immediately put what it calls "a clinical hold" on three trials in the United States, two at Children's Hospital in Los Angeles and one at the National Institutes of Health in Bethesda, Md. The N.I.H. study, and one of the Los Angeles studies, have yet to enroll any patients, he said. The other Los Angeles study is being run by Dr. Donald Kohn, president-elect of the American Society of Gene Therapy. The four children Dr. Kohn and his collaborators have treated all have a form of SCID that is not the X-linked type. But Dr. Kohn said the F.D.A. was correct in suspending his research. "The clinical hold, I think, is the only ethical and responsible course of action until we have more answers," he said.

The F.D.A. will convene a meeting of outside experts next week to discuss the trials, Dr. Noguchi said. He added that other SCID trials had been going on in England and Germany. The German studies have been suspended, but the British research is continuing, he said. At Cincinnati Children's Hospital Medical Center, researchers said they were collaborating with Dr. Fischer to try to determine what, if anything, went wrong in the study. But Dr. Christof von Kalle, who is leading the effort, said it could take months, if not years, for a definitive determination.

Today's announcement came as a panel of independent experts released a study of the safety of clinical trials that was prompted by Mr. Gelsinger's death. The panel, at the Institute of Medicine, called for major reforms, including a federal law that would require all research organizations to develop patient protection programs. Dr. Daniel Federman, a professor of medicine at Harvard Medical School who was chairman of the panel, said the panel was especially concerned about financial conflicts of interest in research. He spoke of a "hodgepodge of protections" that was so haphazard it was impossible to catalog how many Americans were enrolled in research experiments, and how many had been harmed by them.

"At the present time, a lot of people are trying to do a good job, and almost certainly are," Dr. Federman said. "What we are trying to do is raise the level of the system as a whole." Mr. Gelsinger's father, Paul, who has become an advocate for patient protection and reviewed the study in advance of its publication, applauded the work. "I have always felt like what happened to Jesse blew the lid off the can of worms of medical research," Mr. Gelsinger said. "The system needs to be looked at, it needs to be unraveled. This study goes a long way toward doing that."


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Billingsgazette.com 03.10.02, Scientists suspend gene therapy study for possible side effect

By LAURAN NEERGAARD AP Medical Writer WASHINGTON (AP) -

Scientists have suspended studies of the first gene therapy ever to work - a treatment that appears to cure a rare immune disorder called "bubble boy disease" - as they scramble to tell whether the therapy gave a French toddler a leukemia-like side effect. It's unclear if the gene therapy actually caused the boy's illness, although there are clues that a virus used in the treatment may be to blame. No other children given gene therapy for the disease - severe combined immunodeficiency, or SCID - have shown such a side effect. The French boy's gene therapy, performed in October 1999, was successful, giving him a strong immune system. But in late summer, doctors discovered his body had far overproduced a type of white blood cell, a disorder they call leukemia-like. Now 3, he is responding well to chemotherapy, scientists said Thursday.

France and the United States suspended further studies of gene therapy for SCID while they evaluate what happened and notify parents of previous gene therapy recipients of the possible risk. Advisers to the Food and Drug Administration will consult with French scientists and meet next Thursday to debate what steps are needed before the U.S. studies could resume, said Dr. Phil Noguchi, FDA's director of gene therapy. The highly publicized moves were unusual - in studies of regular drugs, many people typically become ill before research is put on hold or generates public debate. But gene therapy has been a publicly charged topic since the 1999 death of 18-year-old Jesse Gelsinger, who was given a different type of gene therapy for another disease. Many scientists now believe that openly discussing potential risks as they're discovered is important to educate people about the new technology.

SCID gene therapy "has been a spectacularly successful endeavor up to this point," said Savio Woo of the American Society of Gene Therapy. If it truly poses a risk of leukemia, "then we have discovered a new enemy. Once we know the enemy, then the experts in the field will...be able to come up with strategies of how to deal with it." SCID is a very rare inhe rited disease, occurring in about 1 in 75,000 births, in which patients' bodies don't make certain proteins crucial to developing disease-fighting immune cells. Without treatment they die very young. The best-known victim was David, Houston's famous "bubble boy" who lived in a germ-proof enclosure until his death at age 12 in 1984

The most severe form, X-SCID, afflicts only boys. Those given a bone marrow transplant from a genetically compatible brother or sister are likely to be cured - but only 20 percent of X-SCID patients have a sibling who's a good match. When boys without a good match undergo a transplant anyway, a quarter die, said Dr. Donald Kohn of Children's Hospital in Los Angeles. Hence the excitement when gene therapy worked in nine of the 10 X-SCID patients treated so far at Paris' Hopital Necker-Enfants Malades. Dr. Alain Fischer drew bone marrow from the boys and culled immune cell-creating stem cells from it. He mixed in a virus containing a gene that makes the immune-system protein the boys' bodies lacked. Injected back into the boys, the stem cells worked properly.

Scientists long theorized - and warned study participants - that cancer might occur if the therapy's virus lodged near certain genes that control cell growth and affected them, too, Kohn said. But with a total of 13 X-SCID gene therapy recipients in France and Britain, and 19 U.S. and Italian children given gene therapy for a related illness called SCID-ADA, the French case marks the first such side effect. All SCID studies use a similar virus. As a result, the FDA has temporarily suspended two X-SCID studies poised to begin at Kohn's hospital and the National Institutes of Health, plus Kohn's own study that recently gave gene therapy to four SCID-ADA patients. Copyright 2002 Associated Press. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.


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Life-Saving Gene Therapy Trial Halted: Treatment Gives French 'Bubble Boy' Leukemia-Like Illness

By Daniel DeNoon, WebMD Medical News, Reviewed By Michael Smith, MD

Oct. 4, 2002 -- A child getting a life-saving gene therapy has developed a strange, leukemia-like illness. The French trial and three similar U.S. trials have been put on hold until more is known. The treatment is the most successful gene therapy yet to reach human trials. It's used to help the so-called "bubble" children with severe combined immune deficiency (SCID). Their immune systems can't fight off germs. Without treatment these children usually die before their first birthday. If SCID children are lucky enough to have a genetically matched family member, a bone-marrow transplant can keep them alive. But such transplants still don't restore them to normal life.

Gene therapy can. The treatment is based on the discovery that a defective gene causes SCID. The space-age treatment takes stem cells from the children and infects them with a genetically engineered virus. This inactivated virus inserts a working copy of the gene into the stem cells and then becomes inactive. Then the blood cells carrying the needed gene are grown to high numbers and transfused back into the children. "These children, if not treated, would never leave the hospital," Philip D. Noguchi, MD, acting director of the FDA's new Office of Cellular, Tissue, and Gene Therapies, tells WebMD. "With this gene therapy treatment they do leave the hospital. Not only that, they go to school, they get vaccinated, they go on with their lives."

The first five SCID children got the gene therapy at Necker Hospital in Paris. It worked for four of them. But now one of these four kids -- a 3-year-old boy -- has developed a leukemia-like blood problem. It looks like the gene therapy caused his white blood cells to grow wildly out of control. Apparently, the virus inserted its gene payload into a "hot spot" in the blood cells' genetic material that triggers uncontrolled cell division. This has always been a theoretical problem with gene therapy but has only recently been seen in animal experiments. It's the first time it's ever happened in human gene therapy.

Does this mean the promise of gene therapy is empty? Noguchi says it isn't so. "With the proven benefit of this treatment, there is a new risk that has appeared," he says. "We now are in a situation of balancing the potential risks vs. the potential benefits. This is where gene therapy is right now." Noguchi says that finding and studying adverse events is one of the main reasons for doing clinical trials in the first place. Looked at in that light, the French trial is not a failure but a success. It has demonstrated a life-saving benefit -- and shown that patients risk paying a high price for it. Is the risk worth it? That remains to be seen. In the fairly numerous cases of this therapy, what has been seen so far is the potential benefits outweigh the risks, says Noguchi.

Four SCID children at Children's Hospital in Los Angeles have already received gene therapy. A second trial at that hospital, and another at the National Institutes of Health in Bethesda, Md., have not yet begun to treat children. All three U.S. trials and the French trial now are on hold until more is known about the new problem. Similar trials are also under way in Germany and in England; the German trial is reported to be on hold as well. This doesn't mean it's too soon to conduct human trials of gene therapies, Noguchi insists.


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Gene Therapy Apparently Leads to New Illness in Boy
By a Washington Post Staff Writer Friday, October 4, 2002; Page A11

Health Officials in U.S., France Suspend Treatments Recently Hailed as Cure for Immune Disorder

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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Le Monde 04.10.02, Suspension de la thérapie génique des "bébés-bulles"

Une forme de leucémie est survenue chez l'un des huit enfants traités avec succès depuis trois ans à l'hôpital Necker, de Paris. La reprise de l'essai dépend des résultats de l'étude des mécanismes qui ont engendré cette complication grave.

Incontestablement , c'est une mauvaise nouvelle. L'équipe des professeurs Marina Cavazzana-Calvo et Alain Fischer (Inserm U 429, hôpital Necker-Enfants-Malades, Paris) a annoncé, jeudi 3 octobre, qu'elle suspendait l'essai clinique de thérapie génique qu'elle menait avec succès depuis plus de trois ans pour guérir des "enfants bulles". Prise en accord avec l'Agence française de sécurité sanitaire des produits de santé, l'Afssaps, cette décision est motivée par la survenue d'une complication chez l'un des huit enfants traités : "une prolifération non contrôlée de lymphocytes". Une situation qui présente des analogies, mais aussi des différences, avec une leucémie.

Comprendre les mécanismes
Agé de 3 ans et traité par thérapie génique à l'automne 1999, l'enfant a dû recevoir une chimiothérapie. Il est actuellement à son domicile. De la compréhension des mécanismes à l'origine de cette complication dépendra la reprise de cet essai ou, au contraire, sa fin, ce qui constituerait un grave revers pour la thérapie génique.

A la fin du printemps dernier, l'équipe de l'hôpital Necker-Enfants malades a constaté chez le quatrième enfant inclus dans l'essai une augmentation de certaines cellules sanguines participant aux défenses immunitaires, les lymphocytes T. L'augmentation touchait en l'occurrence une sous-population particulière appelée lymphocytes T gamma-delta. Il se trouve que, peu de temps auparavant, l'enfant avait eu une varicelle, dont il a guéri, ce qui témoigne d'un bon fonctionnement de son système immunitaire, totalement déficient avant la thérapie génique. Cet épisode pouvait peut-être expliquer le taux élevé de lymphocytes.

Mais cette hypothèse s'est effondrée à la fin du mois d'août, lorsqu'une élévation très importante de la même sous-population lymphocytaire a été constatée par l'équipe médicale. Elle était accompagnée de signes cliniques : augmentation de la taille du foie, anémie, diminution des plaquettes sanguines... Les investigations pratiquées ont montré qu'il s'agissait bien d'une prolifération monoclonale, n'intéressant qu'une lignée cellulaire. En quelque sorte, dans le cas de cet enfant initialement privé de cellules immunitaires, l'effet de la thérapie génique serait allé bien au-delà de ce qui était désiré.

"Nous avons, bien sûr, immédiatement prévenu les parents de l'enfant, raconte Alain Fischer. Ils ont réagi avec courage, combativité et une gentillesse qui force l'admiration. Nous avons également averti les parents des autres enfants, qui, eux, se portent parfaitement bien. Tous sont des gens qui ont parfaitement compris le caractère encore expérimental de notre essai et ont fait le choix de s'engager compte tenu de l'alternative qui leur était proposée." Quelques semaines avant que ne survienne la complication, Alain Fischer indiquait d'ailleurs : "Nous sommes toujours dans une phase expérimentale. Il s'agit de vérifier la sécurité et la pertinence de la technique en analysant le rapport bénéfice-risque." (Le Monde du 10 avril 2002).

L'information a été transmise à l'Assistance publique-hôpitaux de Paris, dont dépend l'hôpital Necker, à l'Afssaps, ainsi qu'aux équipes travaillant à l'étranger dans le domaine de la thérapie génique et à leurs autorités réglementaires. Les Etats-Unis seraient d'ailleurs sur le point, selon le Washington Post, d'interrompre par précaution les recherches en cours sur ces thérapies.

Outre les soins au garçon victime de la complication, la tâche essentielle pour les chercheurs est maintenant d'en comprendre les mécanismes. "Dans les discussions préalables avec les familles, nous leur avons indiqué que le risque de provoquer une prolifération cellulaire existait, mais qu'il était presque théorique, indique Alain Fischer. Nous avions procédé auparavant à quatre essais chez l'animal, et aux Etats-Unis 29 essais de thérapie génique utilisent le même type de virus que celui dont nous nous sommes servi." Est-on en présence du "cas rarissime", ou bien les scientifiques ont-ils sous-estimé le risque de tels accidents ?

Le plus probable, selon Alain Fischer, est que l'événement qui s'est produit soit ce que l'on appelle la mutagenèse insertionnelle. Le principe de cette thérapie génique consiste à infecter les cellules possédant une version anormale du gène au moyen d'un rétrovirus porteur de la bonne version du gène. Le gène de remplacement va s'insérer au hasard dans le génome. S'il le fait à proximité d'un oncogène, il peut entraîner une mutation de l'oncogène et le développement d'une prolifération maligne. Dans le cas précis de l'enfant participant à l'essai de l'équipe de l'hôpital Necker, le gène de remplacement s'est placé au sein du gène LMO2, impliqué dans des formes de leucémie de l'enfant. Or les lymphocytes T gamma-delta qui ont proliféré expriment la protéine codée par le gène LMO2.

La mutagenèse insertionnelle n'est cependant pas forcément le seul facteur en cause, estime Alain Fischer. "La varicelle peut avoir joué un rôle concomitant, de même qu'il n'est pas exclu qu'existent des facteurs génétiques particuliers dans la famille", avance-t-il.

Évaluer les risques
En tout cas, un énorme travail attend les chercheurs. "Nous avons d'ores et déjà mis en chantier, avec des collègues américains et allemands, un programme pour évaluer le risque de tels accidents", précise Alain Fischer. Les équipes vont étudier les caractéristiques des sites d'intégration des gènes de remplacement. Chaque cellule en possède un, mais il y en a en tout une cinquantaine possible. La durée de ce travail devrait se chiffrer en mois, estime le professeur Fischer. "Si le risque apparaît d'un accident sur mille thérapies, cela pourrait être acceptable compte tenu de l'extrême gravité de la maladie, mais ce ne serait plus le cas s'il y avait 10 % de complications majeures."

C'est pour cela qu'Alain Fischer et Marina Cavazzana-Calvo insistent sur le fait que l'essai n'est que suspendu pour l'instant. Ils n'entendent pas céder au découragement. D'autant que, tout en mesurant le coup dur que cela représente pour la thérapie génique, leurs pairs leur rendent hommage : "A tous points de vue, c'est une équipe qui a travaillé aussi bien que l'on puisse travailler", confie Axel Kahn.

Paul Benkimoun

------------------------------------------------

Le Monde 04.10: Pallier les insuffisances de la greffe de moelle Dans le monde, 12 enfants ont été traités avec la technique française.

En février 1999 , pour la première fois au monde, l'équipe du professeur Alain Fischer (Inserm U 429, hôpital Necker-Enfants-Malades, Paris) appliquait une thérapie génique pour soigner un enfant souffrant d'un déficit immunitaire combiné sévère lié à une anomalie génétique sur le chromosome X (DICS-X).

Les garçons expriment donc cliniquement cette maladie rare (un bébé sur 150 000), tandis que les filles peuvent la transmettre. Le garçon porteur de l'anomalie est privé de cellules sanguines spécialisées dans la lutte contre l'infection : les lymphocytes T et les cellules tueuses NK. Ce déficit sévère est responsable d'infections à répétition, qui obligent à placer l'enfant sous une bulle stérile, d'où le terme de bébé bulle.

Mis au point avec la biologiste Marina Cavazzana-Calvo, avec l'aval de l'Agence française de sécurité sanitaire des produits de santé (Afssaps), le protocole visait à contourner les insuffisances de la technique de greffe de moelle. La situation la plus favorable pour la greffe est celle de l'existence, dans la famille, d'une personne ayant les mêmes groupes tissulaires HLA que l'enfant, ce qui rend le don de moelle compatible avec 90 % de chances de succès. Mais un tel donneur potentiel n'existe que dans 20 % des cas. Sinon, la transplantation, même avec un donneur apparenté, n'a que 60 % de chances de succès.

Un taux de réussite jugé insuffisant par l'équipe d'Alain Fischer qui s'est lancée en 1993 dans la mise au point d'une thérapie génique. Après les étapes de l'expérimentation in vitro sur des cellules, puis sur des souris, un protocole avait été mis au point et soumis pour autorisation à l'Afssaps. L'essai avait été autorisé dans un premier temps pour cinq enfants malades sans donneur de moelle ayant les mêmes groupes tissulaires.

La moelle osseuse des enfants a été recueillie et les cellules précurseuses des lymphocytes T et NK ont été isolées. Mises en culture, ces cellules se sont divisées et ont ensuite été infectées par un rétrovirus servant de vecteur au gène de remplacement. Cinq jours après le prélèvement, les cellules ainsi traitées ont été réinjectées dans la circulation sanguine des enfants. Au bout de quelques mois, les premiers lymphocytes T sont apparus dans le sang des enfants traités.

Les deux premiers enfants à en bénéficier, âgés de 8 et 11 mois, ont été traités en février 1999. Les résultats de cette expérience, avaient été publiés dans l'hebdomadaire scientifique américain Science du 28 avril 2000 (Le Monde du 29 avril 2000). Six autres nourrissons, ayant, eux aussi, la forme complète de la maladie avec une absence de lymphocytes C et T, ont par la suite reçu le même traitement. L'un des huit enfants bénéficiant de cette thérapie génique avait connu un problème : les cellules réinjectées avaient été piégées dans la rate, ce qui n'avait pas permis la correction de son déficit. Cet enfant avait finalement reçu une greffe de moelle. En revanche, chez les sept autres, la production de lymphocytes a continué à se faire normalement, jusqu'à la découverte d'une prolifération excessive d'une sous-population particulière de lymphocytes T chez un enfant âgé de 3 ans, ayant reçu la thérapie génique à l'automne 1999.

L'équipe française a exporté sa technique. Des médecins australiens l'ont utilisée chez un nourrisson, et une équipe japonaise s'apprêtait à en faire de même avant que l'essai français ne soit suspendu. Par ailleurs, appliquant une technique proche, l'équipe londonienne du Great Ormond Street Hospital for Children avait annoncé, le 3 avril 2002 le traitement d'un enfant atteint de DICS-X. Elle a ensuite traité deux autres enfants. Au total, 12 enfants dans le monde ont été traités selon ces modalités thérapeutiques.

Paul Benkimoun


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Le Monde 03.10.02, 19:07, Arrêt d'une thérapie génique sur des "bébés-bulles"

Un essai clinique de thérapie génique sur des "bébés-bulles" a été interrompu par précaution par les médecins, l'un des enfants traités à l'hôpital Necker-Enfants malades de Paris ayant développé une maladie "similaire à la leucémie", a annoncé jeudi l'Agence française de sécurité sanitaire des produits de santé. "Chez l'un des patients de cet essai clinique, une complication a été observée. Il s'agit d'une prolifération non contrôlée de lymphocytes qui nécessite actuellement un traitement", indique l'Afssaps dans un communiqué.

Interrogée sur le caractère cancérigène ou non de ce phénomène, la porte-parole de l'Afssaps a précisé qu'elle était "apparentée à une leucémie" mais n'était "pas une leucémie". "Sa signification fait l'objet d'investigations approfondies. Dès la mise en évidence de cette complication, les familles des autres enfants inclus dans cet essai et la communauté scientifique ont été informées. Les autres enfants sont en bonne santé", a précisé l'agence. "Par mesure de prudence et jusqu'à analyse et interprétation du ou des mécanismes responsables, l'essai clinique a été suspendu par le promoteur (l'AP-HP), en accord avec l'Afssaps", ajoute-t-elle.

En avril 2000, une équipe de médecins français avait pour la première fois réussi à corriger un grave déficit immunitaire héréditaire, qui obligait des bébés à vivre dans une "bulle" stérile pour éviter les microbes, grâce à une thérapie génique. Ces résultats, dont s'était fait l'écho la revue américaine Science, avaient été confirmés par le succès du traitement de huit patients. Le déficit immunitaire combiné sévère (DICS X1) lié au chromosome X, maladie héréditaire rare (cinq cas par an en France), ne frappe que les garçons. Caractérisée par l'absence totale de cellules de défense, elle laisse le malade à la merci de la moindre infection, provoquant sa mort en l'absence de greffe de moelle osseuse ou de l'abri en chambre stérile. Le principe de la thérapie génique du déficit immunitaire combiné sévère lié à l'X (DICS-XI) consiste à ajouter aux cellules de la moelle osseuse une copie normale du gène gamma-c. La thérapie génique permet ainsi de reconstituer le stock de globules blancs, des lymphocytes T et d'autres cellules de défense de l'organisme. Les travaux menés par l'équipe des professeurs Alain Fischer et Marina Cavazzana-Calvo ont été les premiers à montrer la possibilité de corriger une maladie par thérapie génique.

SUSPENSION D'ESSAIS EN ALLEMAGNE
La mise au point expérimentale de la procédure a été réalisée entre 1993 et 1999 dans l'unité Inserm U429. L'essai clinique a débuté en mars 1999 à l'hôpital Necker-Enfants malades. Depuis, dix patients ont été traités, dont neuf nourrissons chez lesquels la maladie provoquait une déficience complète en lymphocytes T, indique l'Afssaps. Chez huit d'entre eux, le traitement a permis de reconstituer une immunité efficace des lymphocytes T, ce qui leur permet de mener une vie normale. Chez un patient, il a échoué car les cellules traitées ont été piégées dans sa rate, qui était anormale. Ce patient a reçu une greffe de moelle osseuse qui a permis une reconstitution partielle de ses défenses immunitaires.

Aucun effet secondaire n'a été observé chez ces patients jusqu'à cette année, précise l'Afssaps. La complication rapportée est survenue chez un patient traité en octobre 1999, le quatrième de l'essai. La thérapie génique a permis une reconstitution de ses défenses immunitaires mais, au printemps 2002, un excès d'une population particulière de lymphocytes T a été détecté dans le sang de l'enfant. Leur nombre est devenu très important fin août, entraînant "pour la première fois des signes cliniques, bien que l'enfant soit resté en excellent état général". "Une collaboration internationale se met en place afin d'évaluer rapidement l'impact de cet événement sur cette forme de thérapie génique", a fait savoir l'Agence française de sécurité sanitaire des produits de santé.

Cette complication dans l'essai français survient alors qu'en Allemagne les autorités de santé qui assurent la surveillance des essais de thérapie génique viennent de décider de suspendre tous les essais réalisés avec des vecteurs rétroviraux. Cette décision est liée à la publication au début de l'année par des chercheurs allemands de travaux montrant sur des souris qu'une thérapie génique avec un vecteur rétroviral avait provoqué une prolifération cellulaire ayant des caractéristiques de leucémie myéloïde chronique.


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Boy sickened; gene-therapy trials halted, By Aaron Zitner, Los Angeles Times

WASHINGTON &emdash; A French boy who had been considered one of the few people cured by gene therapy has developed a leukemia-like disease, prompting the Food and Drug Administration (FDA) to halt three U.S. gene-therapy trials.

It is unclear whether the gene-replacement technique caused the boy's new illness. Still, the incident threatens to further dampen hopes for gene therapy, under intense scrutiny since the 1999 death of a teenager in a University of Pennsylvania experiment. Now 3, the French boy is responding well to chemotherapy, scientists said yesterday. In gene therapy, healthy genes are placed in a patient's cells in a bid to compensate for the faulty genes that cause disease. The technique is considered to hold promise for treatment of cancer, hemophilia, AIDS and other ailments.

The French boy had undergone the process as an infant to control "bubble boy disease," a rare immune-system disorder that is fatal if untreated. The boy's immune system rebounded, and he was able to leave a sterile environment &emdash; or "bubble" &emdash; and live at home. But doctors in August found that the boy had developed a leukemia-like illness, the first time the illness appeared in any of the 32 or so patients treated worldwide by gene therapy for the immune-system disease.

Still, FDA officials disclosed yesterday they had halted three U.S. gene-therapy trials this week, days after learning that French authorities stopped trials. Authorities said the incident was not made public until yesterday to give researchers time to talk with patients. Dr. Phillip Noguchi, director of the FDA's Division of Cellular and Gene Therapies, said 150 or so gene-therapy trials are under way in the United States. An FDA advisory panel will discuss the issue Oct. 10.

In severe combined immunodeficiency, or SCID, which has several causes and occurs in 1 in 75,000 births, the patient's body contains a faulty gene and fails to make proteins needed to produce immune cells. Immune cells, in turn, fight disease.


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Gene therapy monitored after leukaemia threat

04 October 2002 LONDON By Health Newswire reporters

The government is monitoring gene therapy trials in the UK following a reported case of leukaemia in a child enrolled in a French study. Advisory committee issues guidance on gene therapy trial

Yesterday (03/10/02), the French gene therapy regulatory authority announced that, following the leukaemia case, the gene therapy clinical trial at the Necker Hospital in Paris has been put on hold. The French trial was attempting to treat x-SCID, a rare inherited disorder caused by a faulty gene, which affects boys. Babies born with the condition lack a working immune system and rarely survive beyond their first birthday.

The UK's Gene Therapy Advisory Committee (GTAC) was alerted to the case on September 16 and immediately carried out a review of gene therapy trials. Only two UK studies, both involving children at Great Ormond Street Hospital in London, were identified as being closely related to the French study. Professor Norman Nevin, chairman of the GTAC, said the French case was "serious" and had prompted the committee to carefully review all available evidence. "In balancing the potential risks and benefits to these children, and in weighing up alternative treatment options, we have decided that, at this time, it would be unjustifiable to withdraw GTAC's approval of the Great Ormond Street studies," he said. "However, in light of this case, GTAC has recommended that additional measures be put in place."

The committee is recommending that the GTAC review developments, on a case-by-case basis, before enrolling any new patients in the studies. Families with children eligible to enter the trials should also be fully counselled so that their choice of treatment can be as informed as possible. Commenting on the gene therapy studies at Great Ormond Street, Prof Nevin said the GTAC had recognised the possibility of cancer resulting from this kind of gene therapy and was satisfied that all participating families had been informed of the risk. "As with all innovative treatments, there will always be the potential for side effects," he said. "GTAC's role in assessing these studies is to balance carefully the potential benefits against the risks, with patient welfare being of paramount importance."

© HMG Worldwide 2002 http://www.health-news.co.uk/


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Boston / Fribourg, Oct 3, 2002

Unfortunate clouds in the sky of gene therapy. (S Rusconi, Oct 3 2002, 3 PM)

the BBC reported that the clinical trial of GT pioneer Alain Fischer has been officially stopped yesterday by French Authorities as a
consequence of the reporting of a leukemia developing in one of the patients three years after the treatment.

More precise investigations are necessary to determine whether the adverse event is directly linked to the gene transfer.
However, preliminary data suggest that the lympho-proliferative disease could have been initiated by an event of insertional
mutagenesis that ultimately progressed into a growth advantage for a sub-population of T-cells.

According to personal communications from people that are close to the laboratory of AF, it has been already ruled out
that the hyper-proliferation had been caused by any adventitious replication-competent retrovirus (RCR).

Oncogenic insertional mutagenesis caused by random integration of transgenic DNA has been one of the most feared negative
potentials of this type of approach. This is the reason why scientists are trying to move towards protocols
where the foreign DNA is either inserted into its homologous position or at least into a specific position of the human genome
(see the recent spectacular example by the team of P Khavari: Ortis-Urda et al, Nature Medicine 8, 1166-1170)

The majority of current vectors for gene therapy cannot yet profit from these new advances, and therefore appear only suitable
for the treatment of otherwise lethal conditions. Any other situation may require a careful assessment of risks-benefits, before
being considered as a valid therapeutic option.

As of today, we are opening this special reporting page on our WEB site dedicated to the adverse event in Paris
and its aftermath, hoping to be useful for interessees in both the scientific community and the public opinion. 

Sandro Rusconi.
.


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Gene Therapy Study Halted Leukemia-like condition found

Newsday.com: October 4, 2002, By Earl Lane WASHINGTON BUREAU

Washington - French researchers have suspended one of the world's most promising gene therapy experiments, for an immune disorder often called "bubble boy" disease, after one of the participants developed a leukemia-like condition.

French health officials said yesterday that all the families with children in the study had been notified of the development. U.S. officials also have decided to delay three gene therapy studies in this country involving the same immune disease.

In the French case, a boy who had been treated in a pioneering study at a Paris pediatric hospital started producing more white blood cells than normal. The boy, now nearly 3, is responding well to chemotherapy, scientists said, and it is not clear yet whether his leukemia-like symptoms are a result of the gene therapy.

"I think it is very important for the scientific community and the regulatory agencies to figure out what really is the cause of this adverse event before we charge ahead blindfolded," said Savio Woo, a past president of the American Society of Gene Therapy and director of gene therapy programs at Manhattan's Mount Sinai School of Medicine.

Woo and others said the French research stood out in a field with decidedly mixed results so far.. In the United States, the field lost some momentum in the wake of the 1999 death of 18-year-old Jesse Gelsinger after gene therapy treatment at the University of Pennsylvania for a rare metabolic disorder. Investigators raised questions about the adequacy of the information conveyed to Gelsinger and his parents.

There is no hint of ethical lapse in the French study, specialists said. But it is sure to raise new concerns about the possible risks of gene therapy. "Any treatment that you use is going to have some element of risk," said Dr. Rebecca Buckley, chief of pediatric allergy and immunology at Duke University Medical Center. "One is going to have to weigh the risk after all the information is in about this particular child" in the French study.

Severe combined immunodeficiency disease, or SCID, came to be called "bubble boy" disease after the experience of a young Texas patient who lived in a plastic, germ-free bubble before succumbing to the disease in 1984 at age 12.

Dr. Alain Fischer and his colleagues in France reported in April 2000 that they had successfully treated two male infants with a form of SCID linked to a faulty gene on the X chromosome. Previously, the only available treatment for that form of the disease had been a bone marrow transplant with a closely matched donor. French researchers took bone marrow from the infants, separated out stem cells and infected them with a virus carrying a replacement gene with instructions for making a vital protein the infants lacked. Once injected back into the boys, the gene-modified cells worked properly and produced the desired immune cells. The French team reported nine of the first 10 infant boys had gained immune function. "To see that 'bubble boy' disease patients can actually go home and live with their families, that is a spectacular success," Woo said.

Leukemia long has been considered a theoretical side effect of gene therapy to treat SCID, Woo said. Any time a virus is used to deliver a replacement gene, there is the chance it will go to the wrong place. If it inserts itself near a gene that controls cellular growth, experts said, it could help promote a cancerous proliferation of cells.

Dr. Philip Noguchi, head of the Food and Drug Administration's division of cellular and gene therapy, said an FDA advisory panel will convene next week to discuss how the French case might affect planned U.S. studies.

Dr. Donald Kohn, president of the American Society of Gene Therapy and a researcher at Childrens Hospital in Los Angeles, said steps might be taken to prevent faulty insertion of the virus carrying a replacement gene. Kohn is a leader of two of the three suspended U.S. studies involving SCID. In one, he said, four children were treated between September 2001 and January 2002. They are doing well, he said, and are closely monitored. The other studies were not yet under way.


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Independent news Update 2: UK continues gene therapy trial despite fears over boy's leukaemia

By Charles Arthur Technology Editor 04 October 2002

Britain defied international opinion last night by going ahead with a gene therapy treatment for seriously ill children that has been suspended by America and France over safety fears. Government scientists said they faced an "ethical dilemma" after a French boy given the therapy in 2000 developed "leukaemia-like" symptoms.

France and the United States said yesterday they were halting trials of the treatment, which has so far been used successfully worldwide on almost 20 people with a rare inherited immune deficiency, sometimes called "bubble-boy disease". It affects babies, who usually fail to survive beyond 12 months without the therapy.

But Professor Norman Nevin, who chairs the Gene Therapy Advisory Committee, said after an all-day meeting that it had been decided that stopping the trials would cause more fatalities than carrying on, even though the exact cause of the French child's illness is not known. The child is receiving chemotherapy and is expected to recover. "An investigation will take 12 to 18 months to find out what happened, and during that time one could be faced with ... children who will die," Professor Nevin said. "Provided the parents are cognisant of the risks, I think that to deny [patients] gene therapy would be unethical."

There are two such trials underway at Great Ormond Street Hospital, which celebrated success in April with Rhys Evans, then 18 months old. The disease, formally known as X-SCID &endash; for X-linked severe combined immunodeficiency &endash; is the only one where gene therapy has consistently worked. The usual treatment is a bone marrow transplant from a sibling, or even a non-family donor. An extract of the patient's bone marrow is treated with a virus carrying the genes needed to revive the immune system. The genes are incorporated into the DNA of the patient's bone marrow, which is reinserted.

Doctors suspect that in the French case the virus interfered with a gene needed for blood production, causing symptoms similar to leukaemia. Dr Bobby Gaspar, consultant immunologist at Great Ormond Street, said the chance of that was less than one in 10 million. "Five years ago there were no successful gene therapies," Dr Gaspar said. "Now we have cures. This is the first step to gene therapy for a wide range of diseases."


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Reuters: UPDATE 1-French stop gene therapy as boy sickens October 03, 2002 06:29 AM ET

(Adds background, further quotes)

PARIS, Oct 3 (Reuters) - French doctors have suspended ground-breaking gene therapy trials after a young boy undergoing the treatment developed a disease similar to leukaemia, France's public health agency said on Thursday.

"A complication was detected with one of the patients at the clinic consisting of an uncontrolled lympho-proliferation which had to be treated," it said in a statement. A spokeswoman at the agency said the disease was similar to leukaemia. "The trials at the clinic have been suspended as a precaution until investigations into the causes have been completed," the statement said. "As soon as the complication was discovered, the families of the other children undergoing such treatment and the scientific community were informed," it said. "The other children are in good health."

The news was a fresh blow in the pioneering domain of gene therapy, which aims to cure disease by replacing faulty genes. A total of eight children were undergoing gene therapy treatment at the Necker-Enfants Malades clinic in Paris.

Asked whether the illness could be linked to the gene therapy treatment, a spokeswoman at the public health agency said: "At the moment, we do not know. We are in the process of investigating it." The children being treated have human severe combined immunodeficiency (SCID) X1, which leaves them without any working immune system. Patients usually live out their short lives in sterile "bubbles" because any infection would overwhelm them.

In early 2000, Dr Alain Fischer of the Necker Hospital in Paris and colleagues said they virtually cured two boys with SCID by restoring their immune systems using gene therapy. They have since tried their method on a third boy, and British researchers also reported they were treating patients. Although scientists have been trying gene therapy for more than a decade, this was the first real success.

Update 2: OTHER CHILDREN IN GOOD HEALTH
A total of eight children had been undergoing gene therapy treatment at the Necker-Enfants Malades hospital in Paris. "As soon as the complication was discovered, the families of the other children undergoing such treatment and the scientific community were informed," the public health body said in its statement. "The other children are in good health."

Asked whether the illness could be linked to the gene therapy treatment, a spokeswoman at the agency told Reuters: "At the moment, we do not know. We are in the process of investigating it." The eight children have human severe combined immunodeficiency (SCID) X1, which leaves them without any working immune system. Patients usually live out their short lives in sterile "bubbles" because any infection would kill them.

In early 2000, Professor Alain Fischer of the Necker Hospital and colleagues said they virtually cured two boys with SCID by restoring their immune systems using gene therapy. British researchers also said they were treating patients. The boy who developed complications began gene therapy in 1999. He was the fourth to be treated at the Necker hospital. Lymphocytes irregularity was detected in the boy's blood early this year and doctors deemed it to be serious in August, the public health agency said.

Although scientists have been trying gene therapy for more than a decade, the French trials appeared to be the first to score a real success. Early trials did not cure anyone, but sometimes helped to deal with certain rare genetic conditions and had not been found to harm patients.


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bayarea.com: Setback for Gene Therapy as France Halts Trials BY STEVE PAGANI Reuters

PARIS - Pioneering gene therapy treatment suffered a big setback on Thursday when France said trials were suspended in the country because a boy receiving the treatment had contracted a disease similar to leukemia.

France's national public health agency said trials had been halted at the Necker-Enfants Malades hospital in Paris after the young boy developed the symptoms. Despite the French announcement, Britain said it would not stop gene therapy trials. It was still unclear whether similar trials in the United States would be halted. "A complication was detected with one of the patients at the clinic consisting of an uncontrolled lympho-proliferation which had to be treated," the health agency said in a statement. A spokeswoman at the body said the disease was similar to leukemia. "The trials at the clinic have been suspended as a precaution until investigations into the causes have been completed," the statement said.

A total of eight children had been undergoing gene therapy treatment at the Paris hospital. The other seven were in good health, the health agency said. Asked if the illness was linked to gene therapy treatment, a spokeswoman at the agency told Reuters: "At the moment, we do not know. We are in the process of investigating it." The halt to trials in France was a fresh blow for gene therapy, which aims to cure disease by replacing faulty genes. Gene therapy research had been recovering from the shock death of an 18-year-old man in the United States in 1999 who had volunteered for treatment to have a rare, inherited liver defect corrected.

SETBACK FOR TRIALS AROUND WORLD

Dr. Nico Wulffraat, an immunologist at the Wilhelmina Children's Hospital in Utrecht who has treated a Dutch boy who was involved in the experimental treatment, said the news was a setback for gene therapy. "It will be a setback but it must be further investigated," he told Reuters. "It must be investigated in depth exactly what is going on."

Authorities in Germany halted trials there this year after scientists found mice used in experiments had developed leukemia-like symptoms. But Britain's Department of Health said it had no intention of halting gene therapy trials in Britain. The government's Gene Therapy Advisory Service Committee (GTAC) has carried out a review of UK gene therapy trials.

"GTAC considers this a most serious case," it said in a statement. "In balancing the potential risks and benefits to these children, and in weighing up alternative treatment options, we have decided that, at this time, it would be unjustifiable to withdraw GTAC's approval of the two Great Ormond Street (hospital) studies," it added.

France's public health body said the families of other children involved in the treatment and the scientific community had been informed as soon as doctors detected complications in the health of the young boy. "International collaboration is under way to try as soon as possible to weigh the impact this incident may have on this type of gene therapy," it added.

The eight children have human severe combined immunodeficiency (SCID) X1, which leaves them without any working immune system. Patients usually live out their short lives in sterile "bubbles" because any infection would kill them. In early 2000, Professor Alain Fischer of the Necker Hospital and colleagues said they virtually cured two boys with SCID by restoring their immune systems using gene therapy.

Although scientists have been trying gene therapy for more than a decade, the French trials appeared to be the first to score a real success. Early trials did not cure anyone, but sometimes helped to deal with certain rare genetic conditions and had not been found to harm patients.


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Associated Press: U.S. Moves to Protect Gene Therapy Patients

Oct. 3 &emdash; By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - U.S. government regulators said on Thursday they were suspending certain gene therapy trials after a French "bubble boy" seemingly cured of his condition developed a disease similar to leukemia.

Researchers said they were not sure whether the treatment had caused the disease in the 3-year-old boy, but to be safe the U.S. Food and Drug Administration was stopping the experiments until they know more. The move came just as a congressionally appointed panel of experts said more needed to be done to protect patients in such experimental trials.

"The clinical halt, I think, is the only ethical course of action until we have the answers," Dr. Donald Kohn, president-elect of the American Society of Gene Therapy, told a briefing by telephone. The boys have severe combined immunodeficiency (SCID) X1, which leaves them without any working immune system. Without treatment, patients usually live out their short lives in sterile "bubbles" because any infection would kill them. It only affects boys, because it is the X chromosome that is faulty. Girls have an extra X that can make up the deficiency.

The gene therapy, which reinforces the children's bone marrow with genetically engineered immune cells, had worked spectacularly well in the children. Boys with X-linked SCID will die by the age of 1 if they cannot receive a bone marrow transplant from a relative with matching blood type. But the three boys in France had gone home and were living normal lives. It was the biggest gene therapy success to date. The French researchers, led by Dr. Alain Fischer of Necker Hospital in Paris, first removed some of the boys' bone marrow and found the stem cells, the source of all the immune system cells. They used a retrovirus to carry normal copies of DNA to correct the defect, and then infused the engineered cells back into the boys.

TREATMENT HAD THEORETICAL RISK OF CANCER
Researchers said this theoretically could cause leukemia, as the virus, which integrates its DNA into the DNA of the target cell, had sometimes attached in a place susceptible to cancer-causing damage. But they stressed that leukemia had never been seen in any gene therapy patient before.

The families of the patients knew of this risk.
Kohn said two trials at his hospital at the University of California Los Angeles involving four children were being suspended while the case was investigated. Other trials. in which children have not yet been treated, were also stopped. The FDA, which regulates gene therapy, has scheduled a meeting next week to examine the case and determine if gene therapy for SCID is a risk to other patients.

The only gene therapy linked death was in 1999, when 18-year-old Jesse Gelsinger died while undergoing experimental gene therapy for a rare genetic liver condition. The case sent the entire gene therapy field reeling. The Institute of Medicine, an independent body that advises the U.S. Congress and federal government, appointed the panel of experts that reported on Thursday that research volunteers were not being protected enough. "It is understandable that the public has come to perceive that research institutions put more emphasis on insulating themselves from liability than on protecting people from harm," committee Chairman Daniel Federman of Harvard Medical School said in a statement. The institute said Congress should establish an independent, advisory body to oversee human medical research and called for a no-fault compensation system for patients injured in experimental trials or their families.

The "informed consent" process where patients sign papers saying they understand the risk of trials needs to focus more on informing patients and less on protecting researchers from liability, the panel said. Sen. Edward Kennedy, a Massachusetts Democrat, said he would introduce legislation strengthening patient protections, especially in the area of gene therapy. "The bill will require special monitoring of adverse events in clinical trials of such research so that threats to patient safety can be identified," his office said.

Gene therapy researchers in the United States did not see the case as a setback.
"While we are going to reap the benefits of gene therapy to treat disease and help patients, we have really got to understand the risks of these trials," said Dr. Savio Woo, a past president of the American Society of Gene Therapy.


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CNNAsia: 'Bubble boy' gene therapy halted

Scientists say treatment may have leukemia-like side effect

Friday, October 4, 2002 Posted: 1:39 AM HKT (1739 GMT)

http://asia.cnn.com/

WASHINGTON (AP) -- Scientists in France and the United States have suspended studies of the first gene therapy to ever work -- a treatment that appears to cure the rare immune disorder dubbed "bubble boy disease" -- because a French boy has developed a leukemia-like side effect.

It's unclear if the gene therapy actually caused the boy's new illness and, if so, how often such a side effect would occur. The 3-year-old boy received gene therapy in his first month of life that worked very well -- he fought off an infection last spring that otherwise could have been life-threatening. But in late summer his body suddenly overproduced white blood cells, a reaction doctors called leukemia-like. He is responding well to chemotherapy, scientists said Thursday.

Nine other children given the same gene therapy at Paris' Necker Hospital are doing well, and no other children worldwide given gene therapy for this disease -- severe combined immunodeficiency, or SCID -- have ever shown such a side effect. But France's public health agency announced Thursday that all the families had been notified about the possible risk.

U.S. regulatory officials have put on hold three SCID clinical trials, one that had treated four children and two others that had been poised to start soon. Several U.S. patients enrolled in similar gene therapy studies dating back 10 years have also been contacted to have the possible risk explained, said Dr. Phil Noguchi of the U.S. Food and Drug Administration. The FDA's scientific advisers will evaluate the development, in consultation with the scientists from Paris, at a meeting next week to determine what additional research or precautions are needed before the gene therapy studies can resume.

A closer look at gene therapy
It is unusual for a single side effect to generate such public attention -- in studies of regular drugs, many people typically become ill before research is put on hold. But gene therapy has been a publicly charged topic since the 1999 death of 18-year-old Jesse Gelsinger in a University of Pennsylvania study. Gelsinger died four days after he was injected with a genetic drug designed to correct a liver disorder.

"Although this is a sobering event," airing potential side effects very publicly is good for the still evolving field of gene therapy, FDA's Noguchi said. SCID gene therapy "has been a spectacularly successful endeavor up to this point," said Dr. Savio Woo of the American Society of Gene Therapy. He said that if doctors discover it did cause the French boy's leukemia-like illness, "then we have discovered a new enemy," and will hunt ways to avoid the side effect.

SCID is an inherited disease occurring in about 1 in 75,000 births. Patients' bodies don't make certain proteins crucial to developing disease-fighting immune cells. The best-known victim was David, a boy from Houston, Texas, who lived in a germ-proof enclosure until his death at age 12 in 1984. Without any treatment, SCID patients die very young. For the most severe form, a type called X-SCID that afflicts only boys, the only treatment is a bone marrow transplant. With bone marrow from a genetically matched sibling, they are likely to be cured -- but only 20 percent of X-SCID patients have such a good match.

When transplants are given to boys without a good match, a quarter die, said Dr. Donald Kohn of Children's Hospital in Los Angeles. Kohn conducts one of the U.S. gene therapy studies now on hold. In contrast, the French gene therapy study has worked in nine of the 10 X-SCID patients treated so far. Lead researcher Dr. Alain Fischer drew bone marrow from the boys, culled immune-creating stem cells from it, and mixed them with a virus in which a gene that makes their missing protein had been inserted. When the boys' cells were injected back into their bodies, they began making immune-system cells properly.

Some U.S. studies have found partial success in treating another form of SCID, called SCID-ADA, that afflicts both boys and girls. All SCID studies use a similar virus to insert the new genes, and scientists long theorized -- and warned study participants -- that cancer might occur if that virus lodged near certain genes that control cell growth, Kohn said. But of 13 X-SCID patients given gene therapy in France and Britain -- plus 19 U.S. and Italian SCID-ADA patients given gene therapy -- the French case is the first such side effect.


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Associated Press: Gene Therapy Study Suspended

By LAURAN NEERGAARD AP Medical Writer

 

WASHINGTON (AP)--Scientists have suspended studies of the first gene therapy ever to work--a treatment that appears to cure a rare immune disorder called ``bubble boy disease''--as they scramble to tell whether the therapy gave a French toddler a leukemia-like side effect.

It's unclear if the gene therapy actually caused the boy's illness, although there are clues that a virus used in the treatment may be to blame. No other children given gene therapy for the disease--severe combined immunodeficiency, or SCID--have shown such a side effect.

The French boy's gene therapy, performed in October 1999, was successful, giving him a strong immune system. But in late summer, doctors discovered his body had far overproduced a type of white blood cell, a disorder they call leukemia-like. Now 3, he is responding well to chemotherapy, scientists said Thursday. France and the United States suspended further studies of gene therapy for SCID while they evaluate what happened and notify parents of previous gene therapy recipients of the possible risk. Advisers to the Food and Drug Administration will consult with French scientists and meet next Thursday to debate what steps are needed before the U.S. studies could resume, said Dr. Phil Noguchi, FDA's director of gene therapy.

The highly publicized moves were unusual--in studies of regular drugs, many people typically become ill before research is put on hold or generates public debate. But gene therapy has been a publicly charged topic since the 1999 death of 18-year-old Jesse Gelsinger, who was given a different type of gene therapy for another disease. Many scientists now believe that openly discussing potential risks as they're discovered is important to educate people about the new technology.

SCID gene therapy ``has been a spectacularly successful endeavor up to this point,'' said Savio Woo of the American Society of Gene Therapy. If it truly poses a risk of leukemia, ``then we have discovered a new enemy. Once we know the enemy, then the experts in the field will...be able to come up with strategies of how to deal with it.'' SCID is a very rare inherited disease, occurring in about 1 in 75,000 births, in which patients' bodies don't make certain proteins crucial to developing disease-fighting immune cells. Without treatment they die very young. The best-known victim was David, Houston's famous ``bubble boy'' who lived in a germ-proof enclosure until his death at age 12 in 1984.

The most severe form, X-SCID, afflicts only boys. Those given a bone marrow transplant from a genetically compatible brother or sister are likely to be cured--but only 20 percent of X-SCID patients have a sibling who's a good match. When boys without a good match undergo a transplant anyway, a quarter die, said Dr. Donald Kohn of Children's Hospital in Los Angeles. Hence the excitement when gene therapy worked in nine of the 10 X-SCID patients treated so far at Paris' Hopital Necker-Enfants Malades.

Dr. Alain Fischer drew bone marrow from the boys and culled immune cell-creating stem cells from it. He mixed in a virus containing a gene that makes the immune-system protein the boys' bodies lacked. Injected back into the boys, the stem cells worked properly.

Scientists long theorized--and warned study participants--that cancer might occur if the therapy's virus lodged near certain genes that control cell growth and affected them, too, Kohn saidBut with a total of 13 X-SCID gene therapy recipients in France and Britain, and 19 U.S. and Italian children given gene therapy for a related illness called SCID-ADA, the French case marks the first such side effect. All SCID studies use a similar virus. As a result, the FDA has temporarily suspended two X-SCID studies poised to begin at Kohn's hospital and the National Institutes of Health, plus Kohn's own study that recently gave gene therapy to four SCID-ADA patients.


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Ananova: 03.10.02 3 pm: Landmark gene therapy treatment halted

http://www.ananova.com/news/story/sm_683654.html

Scientists in the US and France have suspended trials of the first gene therapy to ever work because of a side effect.

The treatment had appeared to cure a French boy with a rare immune disorder dubbed "bubble boy disease". It is unclear if the gene therapy actually caused the boy's new illness which is said to be similar to leukaemia. The boy, a 2*-year-old, received gene therapy in his first month of life that worked very well - he fought off an infection last spring that otherwise could have been life-threatening. But in late summer his body suddenly overproduced white blood cells, a reaction doctors called leukaemia-like. He is responding well to chemotherapy, scientists said.

Nine other children given the same gene therapy at Paris' Necker Hospital are doing well, and no other children worldwide given gene therapy for this disease - severe combined immunodeficiency, or SCID - have ever shown such a side effect. But France's public health agency announced today that all the families had been notified about the possible risk.

US regulatory officials have put on hold three SCID clinical trials, one that had treated four children and two others that had been poised to start soon. Several US patients enrolled in similar gene therapy studies dating back 10 years have also been contacted to have the possible risk explained, said Dr Phil Noguchi of the US Food and Drug Administration. The FDA's scientific advisers will evaluate the development, in consultation with the scientists from Paris, at a meeting next week to determine what additional research or precautions are needed before the gene therapy studies can resume.


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Independent News; Doctors struggle with the ethical dilemma of gene therapy

http://news.independent.co.uk/

Despite controversy and setbacks, the pioneering treatment for congenital disorders remains a prime goal of medical researchers
By Charles Arthur Technology Editor 04 October 2002

Rhys Evans plays like any healthy toddler, having recently celebrated his second birthday. Yet little more than a year ago his parents were unsure he would reach his first. Rhys was born with an inherited disease that left him without an immune system.

The standard treatment is to find a sibling whose bone marrow can be transplanted, so the healthy cells can multiply and spark off the immune system. But Rhys has no siblings, and even that has only a one in three chance of effecting a cure. Non-family donors can provide marrow, but the success rate is even lower, and the side-effects can be serious.

Rhys, however, was lucky. He was successfully given gene therapy by a team at Great Ormond Street Children's Hospital. They extracted some of his bone marrow, used a harmless virus to add working immune system genes to the DNA of those faulty cells, and reimplanted it a few days later. The effects were dramatic. Since then, three other people in the UK with the disease &endash; called X-SCID, or X-linked severe combined immune deficiency &endash; have been successfully treated by the gene therapy team. "Gene therapy was our only real hope," Rhys's mother, Marie, said yesterday. "It has saved Rhys's life."

In France, 11 children with X-SCID have received gene therapy treatment since 1999. All had been well; the future looked promising. But on 16 September came the news that some had feared. Doctors at the Necker hospital in Paris announced that a three-year-old who had received the gene therapy when six months old had developed leukaemia. And the virus used to insert the working genes into his DNA was blamed. The French have halted gene therapy trials to treat X-SCID pending a full investigation. But in Britain, the trials and treatments of boys like Rhys (the disease only affects boys, while girls can be carriers) will go on.

"It's an ethical dilemma," said Professor Norman Nevin, who chairs the Gene Therapy Advisory Council which met in urgent session yesterday to consider the ramifications of the French case. "The [French] investigation into what happened will take 12 to 18 months. During that time, one could be faced with the situation where you're presented with children with this illness who don't have a bone marrow match, who could die in two to three years.

"To deny gene therapy to them would be unethical, provided the parents are cognisant of the associated risks."

Doctors already think they know why the French case occurred and they are hopeful, even confident, that it is not part of a pattern. The reason is that precisely where the working genes are added is a lottery. The human genome of DNA is about three billion base pairs long, reckoned to contain about 35,000 genes. Much of it is apparently a sort of genetic wasteland, without any function we can discern. The virus, with its gene baggage, inserts itself pretty much randomly among the base pairs. The chances of it hitting any one gene are small, because the virus is only about 5,000 base pairs long &endash; about 1/100th the size of the genome.

There is a chance that it could insert itself into a working gene, and deactivate it or create problems, said Bobby Gaspar, a consultant immunologist on the Great Ormond Street team. "Leukaemia is a finite risk of gene therapy trials. But this and a trial in Science with some mice which was a special case are the only known occurrences ... The chances are somewhere in the range of 1 in 10 million to 100 million."

This appears to have been one of those chances. The virus inserted itself near a gene known as "LmO2", which is important for generating blood cells. Leukaemia is cancer of the blood, so it seems that the virus may have turned on the LmO2 gene wrongly. The child is responding to chemotherapy.

This might look like another blow to gene therapy, which was hyped as the perfect means of curing almost any illness. The first treatment to use it came in September 1990. It was used in the US on Ashanthi DeSilva, four, who had a condition called ADA, which also affects the immune system. It appeared to work. Optimism about gene therapy rocketed but her long-term survival probably had more to do with the drugs she kept taking.

Hopes for gene therapy at that time were sky high, but the fervour dimmed when trials produced results that were at best equivocal and at worst negative. Britain's first gene-therapy operation came in 1993 &endash; the year the advisory council was set up &endash; on Carly Todd, when she was 17 months old. That proved disappointing, although Carly is doing well after conventional treatment and a bone-marrow transplant.

The low point was in September 1999, when 18-year-old Jesse Gelsinger from Arizona died four days after starting trials of a gene therapy treatment for an inherited metabolic disorder. The suspicion was that the virus used to carry the genes had reacted with other cells in his body; he showed the signs of a severe immune reaction.

In the ensuing investigations, American researchers were found to be under-reporting the "adverse events" (up to and including deaths) of gene therapy. In the US, funding dried up, and applications to use gene therapy slumped.

In the UK, the Gene Therapy Advisory Council made its own review of the evidence, deciding to allow researchers to persist in their pursuit of this holy grail. Even as the bad news was emerging about Mr Gelsinger, the trials were starting in France to treat X-SCID.

And now gene therapy is starting to come out of its long clinical exile, as a potential, and lasting treatment for illnesses where conventional therapies are limited or rely on donations that may never arrive. To date, there have been 636 completed, ongoing or pending gene therapy clinical trials worldwide. The method varies: sometimes the genes are injected into the body directly (as with Jesse andAshanthi), or sometimes, as with Rhys and the French children, by extracting cells, treating them and reinserting them.

The successes are starting to make their mark. "Five years ago, there were no successful gene therapies," said Dr Gaspar. "Now, we have cures. X-SCID was the first, but there have also been successes with ADA, where two children have been cured in Italy. These are the first steps to gene therapy for a wide range of diseases."

CONDITIONS IN THE QUEUE FOR THERAPY

X-linked SCID Severe combined immunodeficiency (SCID) linked to defective genes on the X-chromosome is an inherited disorder affecting boys. These "bubble babies" lack certain specialised cells of the immune system, making them highly vulnerable to potentially lethal infections.

Haemophilia A blood-clotting disorder which is also inherited and affects mostly boys. Gene therapy trials in the US have shown some patients being able to cut down on medication.

Chronic granulomatous disease This is a group of rare, inherited disorders of the immune system which results in gene defects in cells called phagocytes, which protect against infections by engulfing invading bacteria and fungi. The first UK clinical trials of gene therapies were approved in 2001.

Cystic Fibrosis The most common genetic disease of western Europeans, cystic fibrosis results in a build-up of sticky mucus in the airways and lungs. Researchers have had limited success with nasal sprays loaded with genetically-modified viruses or fatty droplets called liposomes that contain the correct version of the gene.

Genital organ cancers Many cancers of the vulva and cervix are linked with the human papiloma virus, which causes genital warts. Gene therapy trials are trying to stimulate the body's immune system to attack these cancers using a genetically modified form of the vaccinia virus. UK approval was given in 2000.

Liver cancer A trial at the Hammersmith Hospital in London aimed to introduce a tumour-suppressing gene called p53 into cancer cells in order to stem the spread of the liver tumour. A modified common cold virus was proposed but the hospital has since withdrawn its application for approval.


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U.S. Drop Gene Therapy After Boy Falls Ill

Reuters, October 03, 2002 03:34 PM ET By Steve Pagani

http://reuters.com/

PARIS (Reuters) - Pioneering gene therapy for so-called "bubble" patients with no working immune system hit a setback Thursday when France and the United States halted trials after a boy sufferer contracted a leukemia-like disease. Researchers announced the French child's illness and suspended the therapy trials but insisted the hitch, although serious, did not apply to other trials using gene therapy.

The U.S. Food and Drug Administration suspended certain gene therapy trials promptly after hearing the news, but Britain's Department of Health said two such trials there would continue despite the risk, which they said had already been known. "A complication was detected with one of the patients at the clinic, consisting of an uncontrolled lympho-proliferation which had to be treated," France's national health agency said.

The agency said the disease was similar to leukemia and the boy had been treated with chemotherapy.

"The trials at the clinic have been suspended as a precaution until investigations into the causes have been completed," it said in a statement. Professor Alain Fischer, who had been conducting the trials at the Necker-Enfants Malades hospital, told a news conference the problem applied only to the therapy for immuno-deficiency, which leaves patients with no defenses against disease.

They usually live out their short lives in sterile plastic "bubbles" because any infection would kill them. OTHER GENE THERAPY UNAFFECTED "This should not be confused with other types of gene therapy," Fischer said. "The strategies are different, the problems are different and the possible toxicity risks are different."

A total of eight children at the hospital had received gene therapy treatment for the "bubble boy disease." The other seven were in good health, the health agency said. Researchers in the United States reacted to the news by saying they were not sure whether the treatment had caused the disease in the boy but they were stopping trials in the United States until they knew more about what had happened.

"The clinical halt, I think, is the only ethical course of action until we have the answers," said Dr. Donald Kohn, president-elect of the American Society of Gene Therapy. The British government's Gene Therapy Advisory Service Committee (GTAC) said it was not considering stopping two studies taking place at London's Great Ormond Street hospital. "In its original review of those studies, GTAC recognized the possibility of cancer occurring as a result of this type of gene therapy," the GATC chairman Professor Norman Nevin said. A French health agency spokeswoman, asked if the illness was linked to gene therapy, told Reuters: "At the moment, we do not know. We are in the process of investigating it." Gene therapy research had been recovering from the death of an 18-year-old man in the United States in 1999 after he underwent treatment to have a rare, inherited liver defect corrected.

OTHER FACTORS AT PLAY Fischer said other factors besides the gene therapy could be responsible for the boy's illness. The fact he had suffered from chickenpox could have had an effect, Fischer said. Dr. Nico Wulffraat, an immunologist at the Wilhelmina Children's Hospital in Utrecht who has treated a Dutch boy who was involved in the experimental treatment, said the news was a setback for gene therapy. "It will be a setback but it must be further investigated," he told Reuters. "It must be investigated in depth exactly what is going on."

The children in the French and British trials have human severe combined immunodeficiency (SCID) X1, which leaves them without any working immune system. It only affects boys, because it is the X chromosome that is faulty. Girls have an extra X chromosome that can make up the deficiency. In early 2000, Professor Alain Fischer of the Necker Hospital and colleagues said they had virtually cured two boys with SCID by restoring their immune systems using gene therapy. Although scientists have tried gene therapy for more than a decade, the French trials appeared to be the first to score a real success.


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New Scientist: 'Miracle' therapy halted.

http://www.newscientist.com/news/news.jsp?id=ns99992878

A "miracle" gene therapy treatment for children suffering from the fatal "bubble boy" disease has been halted in France, after one of the patients developed leukaemia as a direct consequence of the treatment. However, British doctors argue that without the treatment many of the patients are certain to die, and say a similar trial in UK will continue.

Boys with X-SCID (Severe Combined Immunodeficiency) have a faulty copy of a gene on their X chromosome that makes an immune protein called interleukin-2. As a result, they have no resistance to infection and die unless treated.

In 2000, a team led by Alain Fischer at Necker Hospital, Paris, carried out the first gene therapy treatment, which replaced the faulty gene. It was one of only a handful of successful gene therapy trials in people. In April 2002, the mother of a Welsh boy treated at Great Ormond Street hospital in London described his progress as "nothing short of a miracle". A total of 15 patients, have been treated so was revealed on Thursday that one developped leukaemia.

Uncontrolled production

The boy underwent gene therapy at the age of six months, and contracted chicken pox at two-and-a-half. His white cell count increased in response to the infection, as would be expected. But his bone marrow then started uncontrollably producing these cells.

Gene therapy involves shuttling the gene into a patient's cells using a harmless virus. But transferred genes cannot be targeted to insert into a specific part of a chromosome. And it appears, scientists say, that in this boy the new gene was inserted next to an oncogene, called Lmo2, triggering the leukaemia.

This kind of severe side-effect was not unanticipated. "In its original review the UK Gene Therapy Advisory Committee recognised the 3 April 2002 possibility of cancer occurring as a result Gene therapy causes of this type of gene cancer in mice therapy," says Norman Nevin, GTAC's chairman. But Nevin confirmed that the UK trials will continue: "GTAC is satisfied that all For more related stories parents and children treated were informed search the print edition of this risk and received appropriate counselling prior to treatment." The chances of the gene being inserted next to an oncogene are very low, he adds. Some children with X-SCID are candidates for bone marrow transplant treatments, but others will undoubtedly die without gene therapy. Doctors at Great Ormond Street say two UK patients have died in 2002, because they did not start gene therapy in time. "It is ethically justifiable to go ahead with the Great Ormond Street trials because of the benefits accrued from the treatment," says Nevin.

The full investigation into the three-year-old's leukaemia will take between 12 and 18 months. Doctors say he is responding well to chemotherapy.

Emma Young

 


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Gene Therapy Study Suspended:
Scientists Suspend Studies in France and United States of First Gene Therapy to Ever Work

The Associated Press Oct. 3

http://abcnews.go.com/wire/Politics/ap20021003_871.html

Scientists have suspended studies of the first gene therapy ever to work a treatment that appears to cure a rare immune disorder called "bubble boy disease" as they scramble to tell whether the therapy gave a French toddler a leukemia-like side effect.

It's unclear if the gene therapy actually caused the boy's illness, although there are clues that a virus used in the treatment may be to blame. No other children given gene therapy for the disease severe combined immunodeficiency, or SCID have shown such a side effect.

The French boy's gene therapy, performed in October 1999, was successful, giving him a strong immune system. But in late summer, doctors discovered his body had far overproduced a type of white blood cell, a disorder they call leukemia-like. Now 3, he is responding well to chemotherapy, scientists said Thursday. France and the United States suspended further studies of gene therapy for SCID while they evaluate what happened and notify parents of previous gene therapy recipients of the possible risk.

Advisers to the Food and Drug Administration will consult with French scientists and meet next Thursday to debate what steps are needed before the U.S. studies could resume, said Dr. Phil Noguchi, FDA's director of gene therapy. The highly publicized moves were unusual in studies of regular drugs, many people typically become ill before research is put on hold or generates public debate. But gene therapy has been a publicly charged topic since the 1999 death of 18-year-old Jesse Gelsinger, who was given a different type of gene therapy for another disease.

Many scientists now believe that openly discussing potential risks as they're discovered is important to educate people about the new technology. SCID gene therapy "has been a spectacularly successful endeavor up to this point," said Savio Woo of the American Society of Gene Therapy. If it truly poses a risk of leukemia, "then we have discovered a new enemy. Once we know the enemy, then the experts in the field will...be able to come up with strategies of how to deal with it."

SCID is a very rare inherited disease, occurring in about 1 in 75,000 births, in which patients' bodies don't make certain proteins crucial to developing disease-fighting immune cells. Without treatment they die very young. The best-known victim was David, Houston's famous "bubble boy" who lived in a germ-proof enclosure until his death at age 12 in 1984. The most severe form, X-SCID, afflicts only boys.

Those given a bone marrow transplant from a genetically compatible brother or sister are likely to be cured but only 20 percent of X-SCID patients have a sibling who's a good match. When boys without a good match undergo a transplant anyway, a quarter die, said Dr. Donald Kohn of Children's Hospital in Los Angeles. Hence the excitement when gene therapy worked in nine of the 10 X-SCID patients treated so far at Paris' Hopital Necker-Enfants Malades.

Dr. Alain Fischer drew bone marrow from the boys and culled immune cell-creating stem cells from it. He mixed in a virus containing a gene that makes the immune-system protein the boys' bodies lacked. Injected back into the boys, the stem cells worked properly.

Scientists long theorized and warned study participants that cancer might occur if the therapy's virus lodged near certain genes that control cell growth and affected them, too, Kohn said. But with a total of 13 X-SCID gene therapy recipients in France and Britain, and 19 U.S. and Italian children given gene therapy for a related illness called SCID-ADA, the French case marks the first such side effect.

All SCID studies use a similar virus. As a result, the FDA has temporarily suspended two X-SCID studies poised to begin at Kohn's hospital and the National Institutes of Health, plus Kohn's own study that recently gave gene therapy to four SCID-ADA patients. Copyright 2002 The Associated Press.

 


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Position of the American Society for gene therapy (ASGT)
October 3, 2002

Dear ASGT Member:

Please find below a very important media statement
that the Society has issued today, October 3, 2002 in relation to an
adverse event in a clinical gene therapy trial.

Serious Adverse Event in a Clinical Trial of Gene Therapy for the
X-Linked Form of Severe Combined Immune Deficiency
Disease (XSCID)

A serious adverse event has been observed in the clinical trial of gene therapy for the X-linked form of severe
combined immune deficiency disease (XSCID) being performed by Alain Fischer, MD and colleagues at the Hôpital Necker
Enfants Malade, Paris, France.

The American Society of Gene Therapy (ASGT) supports the Food and Drug Administration's decision to put a clinical
hold on similar trials in the same disease in the U.S. until more is known about the adverse event. Other gene
therapy trials are unaffected by the clinical hold.

As with all clinical research, patient safety is of paramount importance and all possible efforts must be
made to minimize risks. The ASGT is mobilizing its members with scientific and clinical expertise in this
area of research to work diligently with the relevant federal regulatory agencies to thoroughly investigate
this adverse event, and conduct a broader examination on the safety of using this type of integrative gene
transfer vectors to transfer genes into the bone marrow cells. Both the process and the findings of
this investigation should be totally transparent and available to the public.

SCID, often referred to as "bubble baby disease", is a genetic disease with severe defects in T cell and B cell
immunity. If untreated, SCID is usually fatal in the first years of life, due to severe and recurrent
infections. The treatment of choice for SCID is a bone marrow transplant from a normal brother or sister who
is a perfect "tissue-type" match. Unfortunately, the majority of patients with SCID lack such a matched donor
and must turn to other treatment options. Use of bone marrow from a parent or an unrelated donor is successful
in only 60-70% of infants. Moreover, there is the risk of development of lymphoma in bone marrow transplant
patients who receive cells from a donor who has had infectious mononucleosis. Thus, investigations of new
treatments such as gene therapy are vital to improve the survival of these patients.

To improve the outlook for infants who lack a matched sibling donor, gene therapy has been under investigation
in the United States and abroad. The gene therapy procedure involves insertion of the corrective gene into
the patient's own bone marrow stem cells followed by transplantation, thus avoiding transplant rejection. The
corrected stem cells produce immune competent T and B cells thereby achieving effective immunity. Notably, the gene
transfer approach of the Paris clinical trial has led to life-saving immune recovery in 10/11 (approximately 90%)
of the treated infants, who were able to go home.

One of the subjects has developed what appears to be T cell leukemia-like illness, about three years after
the gene therapy procedure. The child is now receiving chemotherapy. The cause of this leukemia is not yet
known but there is very preliminary evidence to suggest that it may be consequence of a process termed "insertional
oncogenesis." A retroviral vector was used to carry the gene into the patient's bone marrow cells. Retroviral
vectors insert into the chromosomes of the cells they enter, which allows the gene they carry to be copied and
passed on to all the cells which are produced from the bone marrow stem cell. Retroviruses can contribute to
cancerous changes in a cell if they insert into the cell's chromosomes near to a cellular gene that regulates growth.

Insertional oncogenesis has been previously thought to be a very unlikely but possible risk with the type of vector
used in this study, since these vectors cannot reproduce themselves and so cannot repeatedly insert into the cell's
chromosomes, the process that is most likely to lead to a malignant change.

No evidence of leukemias or other forms of cancer were seen in the extensive pre-clinical studies performed
before the trial was begun. Although no similar adverse event has been thought to be related to the gene therapy
in more than 100 patients, the success rate and detail of follow-up has been much more extensive in the Fischer
trial. This risk of cancer as an adverse side-effect of gene therapy is stated explicitly in the informed consent
statements that describe the risks and potential benefits to patients and their families.

Further investigation is necessary to understand whether the gene therapy procedure is the cause of the leukemia.
Dr. Fisher and a number of other independent experts are working to try to identify the events that led to
lymphoproliferative disease in one patient and whether there existed any predisposition to develop leukemia that
was enhanced by the gene therapy. In addition, these investigations will attempt to determine whether this
retroviral gene therapy procedure involves unique risks that may distinguish this procedure from other
retroviral-mediated gene therapies carried out in other patients. It will be necessary to weigh the frequency
of this type of complication from gene therapy against the risks and benefits of other methods of treatment
and determine which will be best for patients.

The American Society of Gene Therapy is a professional,
non-profit medical and scientific organization dedicated
to the understanding of gene therapy and to promoting
professional and public education in this field.

Website: http://www.asgt.org

 


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BBCNews: Leukaemia alert over gene therapy

Rhys Evans was cured of the condition earlier this year Gene therapy trials in the UK will be closely monitored after a child undergoing treatment in France developed cancer. Members of the Department of Health's gene therapy advisory committee (GTAC) said on Thursday they had decided against halting trials.

Both France and the United States have suspended gene therapy trials in children with potentially life-threatening x-Severe Combined Immunodeficiency syndrome (x-SCID). It came as doctors revealed that a three-year-old undergoing treatment in Paris had developed leukaemia. The infant was one of eight children being treated at Necker-Enfants Malades clinic in Paris for x-SCID.

Mutated gene
Children with x-SCID or "bubble boy" disease are born without an immune system. The condition, which is caused by a single mutated gene, means children must live in sterile conditions or risk picking up a life-threatening infection.

The treatment has been carried out successfully in the UK.
Earlier this year, doctors at Great Ormond Street Hospital in London cured 18-month old Rhys Evans, from Cardiff, of the condition. He celebrated his second birthday this week. The three-year-old who has developed leukaemia received gene therapy in his first month of life. The treatment was considered to have worked well. He had fought off an infection last spring that could have threatened his life.

However, in recent months his body started to produce too many white blood cells which is similar to children who develop leukaemia. According to doctors, the boy is responding well to chemotherapy. But members of the GTAC said extra precautions would now be taken in the UK. In a statement, the committee said trials at Great Ormond Street Hospital, which currently involve three children and one adult will be allowed to continue. Committee chairman Professor Norman Nevin said: "GTAC has carefully reviewed all the available evidence.

"In balancing the potential risks and benefits to these children, and in weighing up alternative treatment options, we have decided that, at this time, it would be unjustifiable to withdraw GTAC'S approval of the two Great Ormond Street studies. "However, in light of this case, GTAC has recommended that additional measures be put in place."

Expert review
A sub-committee is being established to review all UK studies involving this type of gene therapy. Families with children eligible to enter the trials will also be fully counselled about this new development so that their choice of treatment can be as informed as possible. Professor Nevin said that cancer was always seen as a possible side-effect of this type of gene therapy. He added: "As with all innovative treatments, there will always be the potential for side-effects."

Dr Bobby Gaspar of Great Ormond Street Hospital welcomed the committee's decision. "If we stop these studies now we will be denying extremely effective therapy to children and they may suffer as a result of not receiving this therapy. Ethically we believe it is the right thing to go one," he told the BBC. That view was echoed by Marie Evans, the mother of Rhys who has undergone the treatment. "If they stop something just because one child has an adverse effect at the end of the day medicine and the world just doesn't go on," she said.