somatic gene therapy

.January 2003, second adverse event in Paris!

(Zweiter Leukaemie-Fall in Paris!)
(Un deuxième cas de leucémie à Paris!)

Last update: Feb 14, 2004

This page is regularly updated since October 2, 2002 (public declaration of first adverse event) with facts, comments & reactions. You are welcome to send your feedback by email to Sandro Rusconi


stained white cells smear, with leukaemic cells

Good will, bad luck, lots of lessons and more....

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.

By January 14, 2003, we unfortunately hear that a second case similar to the one reported in October has emerged in the cohort of treated patients. Although the role of insertional mutagenesis as a sole causative agent for these cases remains to be elucidated, the picture is getting somewhat worrysome.

Comments by SR on second case (19.1.03, The easy wisdom..., )
Chronology and Facts (update 04.12.03)
Comments by SR on first case (October 2002)
Description of the research of A.Fischer
Lecture Dr. Cavazzana on the first reported case (ESGT meeting, 10.10.02)

Media Box 02
reaction from the press and institutions to
the 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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Chronology of case I

Chronology of case II

Facts and questions after case 1

Facts and questions after case 2

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The easy wisdom of the days after...

Comments by Sandro Rusconi to the second case of leukaemic adverse effect emerging from the gamma(C) treated cohort

In experimental biology we are acquainted with the impression that 'one isolated case is interesting, a second one makes a rule, a third one makes a dogma'. With the emergence of a second case of adverse hyperproliferation reported in the X-SCID patients treated by A Fischer with retroviral transduction of the gene encoding the gamma(c) receptor we have come to the second stage. It sounds almost like a rule. And rules always call for rather precise explanations. The most striking observation is the report that also in this second independent case the hyperproliferating cells seem to bear an insertion of the recombinant provirus in the vicinity of the LMO2 locus. This cannot be a simple coincidence and raises the following questions:

There are many reasons (briefly explained below) that prompted me to think that this second case speaks very much in favour of (d) and much less in favour of a simple random mutagenesis event. I was pleased to learn after some reading and some recent correspondence with expert immunologists (such as Pascal Meylan, Lausanne) and internationally recognised gene therapists (such as Claudio Bordignon, Milano) that there is some solidity in the idea that the therapeutic gene used for this therapy could indeed contribute to the emergence of the adverse effect. In the press releases of both the ESGT and the German regulatory experts , the possible contribution of the particular transgene used in this trials to the adverse effect is also clearly mentioned. It is always good to feel well accompanied in such a hypothesis.

The LMO2 gene encodes for a receptor that responds to several lymphokines and promotes cell proliferation and anti-apoptotic status. From this point of view, the gamma(c) gene is effectively a bona-fide proto oncogene. From here to believe that a mild overexpression of the gene in combination with a slight overexpression of the LMO2 gene (another known proto-oncogene) induced by random insertional mutagenesis in the vicinity of its locus could give a hyper-proliferatory kick and a survival advantage to a cell, the step is very small. Notwithstanding, it remains that the use of this gene as a therapeutic gene was obligatory for a disease like the X-SCID which is caused by its loss of function. Therefore there cant' be any a priori accusation of improper choice of the reagents by the team of Fischer. I am in fact absolutely sure that these people were and still are perfectly aware of this eventuality. I still have to read the scientific part of the clinical protocol, but I believe that such a consistent appearance of the adverse event most likely belonged only to the 'worst case scenario' in the risk-benefits calculation for this kind of treatment.

Some numbers: If we assume that even only 10% of the about 100 millions transduced and reinfused cells were bearing an independent integration event, we must accept that overall there has been a random insertion for every 300 basepairs of the genome. Thus, the chance to hit any given proto-oncogene is essentially 100% in the whole cell population. The rest is only matter of selective advantage. The statistics of random integration foresees that even if the regulatory region that drives the expression of the transgene is carefully designed to avoid overexpression, the position-effects of the genome will make this expresssion fluctuate from silence to x-fold overexpression. Furthermore, the intrinsic mutation rate of retroviral systems (about 10exp(-4) per replication because it occurs in absence of proofreading) may add to the complexity. A 3 kb gene will have a chance of 1:3 per gene to be mutated , and 1:10 to be altered in a non-silent manner. This could further enhance the probability that a foreign gene encoding a signal transducer could become genuinely proto-oncogenic by gain of function.

It is absolutely crucial that the specialist sort out whether the adverse event is a general phenomenon or a specific one.

If things go as anticipated by the above mentioned hypothesis, the 'best case scenario' that we can currently offer to the gene therapists is that the adverse events observed in the Paris' trial are indeed specific to the treatment and to the vector and transgene used in this trial. According to this view, there should be a good chance that other types of therapy (where other types of genes are transferred) would be linked with a much lower (and probably more acceptable) risk of pro-oncogenic complications.

Obviously, random insertion in the genome is not and will never be without risks, but perhaps we have seen a very peculiar case of synergism with this particular trial. «All this is easy wisdom of the day after, Mr. Rusconi !» you may think. You're right. Hopefully, the persistence of the insertional mutagenesis risk shall encourage gene therapists in keep searching innovative solutions and ameliorations of the gene transfer procedures. On the other hand, if the adverse effects can be linked to the peculiarities of the Paris' approach rather than to a general property of retrovitral gene transduction, this awareness shall encourage the competent authorities to withdraw the halt to some current clinical trials.

January 19, 2003, Sandro Rusconi, Director of the Swiss National Research program 37, somatic gene therapy

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European Society of Gene Therapy (ESGT), Press release, January 17, 2003, For immediate release

Contact: Bernd Gansbacher, President, 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,

Reports of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID)

Position of the European Society of Gene Therapy (ESGT)

News of a second, serious adverse event in a clinical trial of gene therapy for inherited, X chromosome-linked Severe Combined Immunodeficiency (X-SCID) were made public on January 14th. The US Food and Drug Administration, the Office for Biotechnology Activities at the National Institutes of Health, and the American Society for Gene Therapy have taken the unilateral decision to publicly release the information they had received on December 20th, 2002 from 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 had informed their scientific colleagues that the fifth of the eleven patients under treatment developed a T-cell leukemia, and was receiving chemotherapy. The FDA has placed a temporary halt on gene therapy trials using retroviral vectors in blood stem cells. Following the US disclosure, the French Medicinal Product Safety Agency has issued a press release reporting the second case on January 15th. (

This is the second serious adverse event to be reported in this trial. The first one was reported on October 2nd, 2002, when the French group issued a press release indicating that the fourth patient under treatment had developed a monoclonal lymphoproliferative disease (a leukemia-like disorder). The French investigators decided to share with the scientific community their data on this first adverse event by presenting the case at the ESGT annual meeting held in Antibes (France), October 13-16. A transcript of the presentation, and the discussion that followed, is available soon on the ESGT web page at ESGT fully supported the investigators' and French regulatory authority's decision to put the trial on hold pending further investigations (see the ESGT positions posted on October 8th and 25th on the ESGT web site at

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.

One of the patients (the fourth) 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 followed by the team. The causes of this adverse events have not been conclusively established so far., although Tthe investigators reported announced that the retroviral vector used to transfer the therapeutic gene into the patient's hematopoietic cells was found, in the malignant cells, inserted in a gene (called LMO2) known to cause T-cell leukemia if activated inappropriately, for instance as a consequence of a chromosomal translocation. The investigators speculated that the insertion of the retroviral vector might have caused an abnormal expression of LMO2, which in turn might have triggered the leukemic transformation. Other factors could have potentially contributed to the malignant transformation, including malfunction of the therapeutic gene, which encodes a common subunit of various T-cell growth factor receptors. In her presentation to the ESGT annual meeting, Dr. Cavazzana-Calvo mentioned a history of childhood tumors in the patient's family, and reported an episode of chickenpox infection in this patient preceding the occurrence of the malignancy, which 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, and that the leukemic cells carried an additional molecular abnormality, a translocation between chromosomes 6 and 13, which does not involve the LMO2 gene.

The second adverse event involves a 3-yr old patient who was treated at the age of 3 months for X-SCID following a gene therapy protocol almost identical to that of patient 4, who developed the first leukemic disorder. In the month of December 2002, an monoclonal alpha/beta monoclonal, uncontrolled, monoclonal alpha/beta T-cell proliferation was found in this patient. Similar to the first adverse event, also in this case, the retroviral vector was found integrated within the LMO-2 gene in these proliferating T-cells.

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, including those addressing another form of severe combined immunodeficiency (the ADA-deficient SCID), which started in the U.S. and in Europe more than a decade ago.


The position of ESGT

Patient safety is the major consideration in early clinical studies, and all possible efforts must be made to minimize the risks for the patients involved. The occurrence of leukemic complications in two out of ten treated patients in less than a year is a clear sign that the gene therapy treatment for X-SCID, as it was originally designed, involves an unforeseen and unexpectedly high risk of causing cancer. The repeated involvement of the LMO-2 gene as a site of insertion in the proliferating T-cell clones strongly suggests that the abnormal expression of this gene constitutes a high risk in the context of this treatment for this particular disease. ESGT, as an association of professionals dedicated to the development of gene and cell therapies, encourages and fully supports the efforts of the French investigators and their collaborators to understand the causes of these adverse events. ESGT members are ready to work with European regulatory authorities to thoroughly investigate this series of adverse events, and to evaluate any implications they might have for other gene therapy trials using vectors and procedures similar to those used by the French group.

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. As the history of this trial demonstrates, risk assessment cannot be based entirely on the results of pre-clinical investigation.

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For Immediate Release January 14, 2003 Contact: Joan Geiger, ASGT Director of Communications, 414-278-1341


(Milwaukee) A second serious adverse event, similar to the one reported in September 2002, has been observed in a clinical trial of gene therapy for the X-linked form of severe combined immune deficiency disease (XSCID) being performed by Alain Fischer, MD, Marina Cavazzanna-Calvo, MD and colleagues at the Hopital Necker Enfants Malade, Paris, France.

In response, the Board of Directors of the American Society of Gene Therapy (ASGT) supports the Food and Drug Administration's (FDA's) decision to put protocols of this type on clinical hold until further assessment of risk to patients can be assessed and has initiated a comprehensive review to understand the cause of the leukemia developed in two of the 10 infants treated for XSCID by gene therapy. The ASGT also encourages heightened caution in the further enrollment of new subjects in other clinical trials involving retrovirus-mediated gene transfer to hematopoietic cells and urges all investigators conducting retroviral mediated gene therapy to review available data and reassess the risks and benefits of their clinical trial. If warranted, informed consent documents should be revised after consultation with the appropriate regulatory bodies.

ASGT will establish an ad hoc committee of scientists to collect and analyze the relevant data that exists from among many individual studies performed world-wide, including experimental research studies in animals and the relevant clinical trials. The accumulated data and analyses will be presented in a scientific symposium at the 6th annual meeting of the ASGT in Washington DC, June 2003. Understanding the mechanisms that underlie the development of leukemia may lead to improved methods of gene therapy for this inherited immune deficiency disease that can minimize the risks but preserve the benefits that have been seen in this trial. As with all clinical research, patient safety is of paramount importance and all possible efforts must be made to minimize risks.

The results of the deliberations of the ad hoc committee will also be posted publicly at the society's web-site ( and would be available to regulatory and advisory agencies to assist in their assessments of the risks and benefits of this new form of therapy. ASGT continues to work closely with the FDA and Office of Biotechnology Activities/National Institutes of Health to examine the scientific, medical and ethical issues involved with gene therapy studies.

The clinical trial of gene therapy for X-linked severe combined immune deficiency (XSCID) performed by the French investigators still has seven of 10 subjects in good health with their immune systems restored by the gene treatment (one child was too ill at the time of the procedure to benefit). These findings highlight the potential of gene therapy to correct this otherwise fatal immune disorder without complications such as graft rejection that may be seen when hematopoietic stem cells from another donor are used in a "standard" bone marrow transplant approach.

A key scientific question to be explored is why this problem has only been seen so far in this study of infants treated for XSCID, but not in any of the other clinical trials using retroviral vectors targeted to hematopoietic stem cells (or any other trial of gene therapy). There may be unique unrecognized features of the specific gene (called GammaC, which encodes a T cell growth factor receptor), the specific disease (XSCID), the subjects' age (infancy), or some aspect of the gene transfer methodology that increased the risks of triggering leukemia.

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 healthy brother or sister who is a perfect "tissue-type" match. Unfortunately, most 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, with a significant number of subjects gaining only partial immune restoration. 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 rate 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 hematopoietic stem cells from bone marrow 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 led to life-saving immune recovery in 9/10 (90%) of the treated infants, who were able to go home.

However, one of the subjects of this gene therapy trial was observed in September 2002 to have developed T cell leukemia, about three years after the gene therapy procedure. Leukemia is a form of cancer in blood-forming cells. In December 2002, a second subject was diagnosed with a similar leukemia-like illness. Both subjects have been treated with conventional chemotherapy to attempt to eliminate the leukemia.

Dr. Fischer and a number of other independent experts are working to try to characterize the events that led to leukemia in these patients and whether there existed any predispositions to develop leukemia that was enhanced by the gene therapy. 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. It is widely believed that development of cancer in humans depends on a complex series of genetic and biological events that are not completely understood, and therefore, it is not possible, at the current time, to fully understand the role of the gene transfer process in the development of the leukemias that have arisen in the two patients. Nevertheless, based on extensive studies of animal models of cancer, and particularly the association between the disregulated expression of a number of specific genes and the development of different human cancers, it is highly likely that the insertion of the retroviral vectors into the specific regions of chromosomal DNAs observed in those two patients contributed significantly to the development of their cancers

A retroviral vector was used to carry the gene into the patients' hematopoietic stem cells from their bone marrow. Retroviral vectors insert into the chromosomes of the cells they enter, which allows the gene they carry to be stably copied and passed on to all of the cells that are produced from the hematopoietic stem cell. Retroviruses can contribute to cancerous changes in a cell if they insert into the cell's chromosomes near a cellular gene that regulates growth. The complication of cancer or leukemia was previously thought to be a possible but very unlikely 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. 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. No evidence of leukemia or other forms of cancer were seen in the extensive pre-clinical studies performed before the trial was begun.

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.

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Press Release Paul-Ehrlich-Institut, Federal Agency for Sera and vaccines Publisher: Unit A/1 of the Paul-Ehrlich-Instituts (Press and Public Relations) ·

Paul-Ehrlich-Straße 51&endash;59· 63225 Langen, Germany · Phone: +49/6103 / 771030 Fax: +49/6103 / 77 1262 E-mail: Homepage: Press law responsibility: Dr. Susanne Stöcker 15th January 2003 4 pages Paul-Ehrlich-Institut Paul-Ehrlich-Straße 51-59 Telefon +49/ 61 03/77-0 Bundesamt für Sera und Impfstoffe D-63225 Langen Telefax +49/ 61 03/77-1234 Federal Agency for Sera and Vaccines Postfach D-63207 Langen

Joint Press Release by the Paul-Ehrlich-Institut and the German Medical Association (Bundesärztekammer) Second Case of Leukaemia after Gene Therapy in France Interferes With Continuation of a Clinical Study Involving the Use of Retroviral Vectors in Germany

On Friday, 20th December 2002, Dr. Alain Fischer, Hôpital Necker des Enfants Malades, Paris, informed the Paul-Ehrlich-Institut on the diagnosis of a leukaemia-like disease in a second patient treated by gene therapy. Within a day and in agreement with the Commission for Somatic Gene Therapy (Kommission Somatische Gentherapie (KSG)) of the Scientific Council of the German Medical Association, the Paul- Ehrlich-Institut informed the principal clinical investigators of clinical studies using live retrovirally modified cells in Germany within a day. After the first case of leukaemia in France, the continuation of the clinical studies was considered possible for three out of 16 notified clinical studies in Germany involving the use of retroviral vectors (see Joint Press Release issued by the Paul-Ehrlich-Institut and the German Medical Association of 22nd November 2002; ").

Until the second case of leukaemia will have been further clarified, the KSG and the Paul-Ehrlich-Institut will keep on clinical hold the CGD study (a congenital immune deficiency disease called Chronic Granulomatous Disease, see "Background Information" in the Appendix). Similar to the study in France, the CGD study uses retrovirally modified blood stem cells the risk of which is tentatively, and until further information will be obtained, estimated to be higher than that of other retrovirally modified cells. The continuation of two studies for the treatment of 'Graft-versus- Host Disease' (GvHD) by lymphocytes using a drug-inducible cell-killing (suicide) gene will be recommended shortly on condition that the appropriate patient information leaflet is again modified (to include a mention of the second case of leukaemia) (see "GvHD treatment by 'suicide gene' transfer and administration of Ganciclovir" in "Background Information"). The clinical hold of all other clinical studies in Germany using live retrovirally modified cells will be maintained. Some of these studies have already been completed.

Applications for two new studies using modified lymphocytes in HIV infected individuals and modified (synovial) cells from joints in patients suffering from rheumatoid arthritis have been submitted. The recommendations of the KSG and the decisions of the Paul-Ehrlich- Institut on those two studies and the above-mentioned CGD study will be discussed in February.

According to Prof. Klaus Cichutek, Vice President of the Paul-Ehrlich- Institut and chairman of the KSG, "the news about the second case of leukaemia in France marks a major setback for gene therapy involving the use of retrovirally modified blood stem cells". As he stated, a final assessment of the frequency of the occurrence of leukaemia following in vivo transfer of retrovirally modified blood stem cells could not currently be made. However, as he explained, with the exception of the two cases of leukaemia in France, no further cases of cancer had been reported or become publicly known, which had been suspected to have been caused by the use of particular vectors or cells. According to one of the possible, although currently unproved explanations, the leukaemias diagnosed during the SCID-X1 study could be induced by the use of retroviral gene transfer in blood stem cells in conjunction with other cell-growth promoting conditions. These other conditions may include the therapeutic gene used as an important critical factor. From that point of view, these cases would have to be investigated very thoroughly to gain certainty on whether stem cell gene therapy used in other life-threatening diseases would bear the same risk.

The Paul-Ehrlich-Institut and the KSG had been informed on a case of a patient in France developing a leukaemia-like disease after treatment with gene therapy for the first time in September 2002. In this French study, children suffering from the congenital immune deficiency disease SCID-X1 (type X1 of the "Severe Combined Immunodeficiency Disease") were treated with autologous (patient's own), modified blood stem cells. In this congenital disease, the normal functionality of the blood stem cells is restored by retroviral transfer of the intact form (allele) of the defective gene underlying the disease. The study has been on hold up until the present day. Following this case of leukaemia, the KSG last had discussed a possible continuation of the affected clinical studies involving gene therapy in Germany with the Paul- Ehrlich-Institut on the basis of the above results in November 2002.

Prof. Dr. Klaus Cichutek Vice President of the Paul-Ehrlich-Institut Chairman of the "Commission for Somatic Gene Therapy" (Kommission Somatische Gentherapie (KSG))

Background Information:

Since the clinical hold of all 16 studies involving the use of live retrovirally modified cells, three modifications of protocols (amendments) and one new application for the continuation of a study as well as one new application for a new study (application at the KSG and/or submission pursuant to Section 40 German Drug Law (AMG) at the Paul- Ehrlich-Institut) have been submitted in Germany.

1. Gene therapy of a monogeneic congenital disorder:
For the treatment of the life-threatening hereditary disorder (CGD) "Chronic Granulomatous Disease"), autologous blood stem cells are transplanted, the gene defect of which was corrected by retroviral transfer of a functionally intact gene. This serves to alleviate, or even cure, the congenital immune deficiency.

Status: 1 registered study; on hold;
A modification of the protocol is available and is to be discussed again.

2. GvHDGvHD treatment by 'suicide gene' transfer and administration of Ganciclovir:
Suppression of graft-versus-host disease during the treatment of leukaemia by transplantation of donor (allogeneic) blood stem cells and lymphocytes. The transfer of allogeneic donor lymphocytes is a conventional tumour therapy which, after prior chemotherapy and stem cell transplantation, leads to a suppression of leukaemia (donorversus- leukaemia effect). However, a strong immunological reaction (Graft-versus-Host Disease; GvHD) caused by the transplanted lymphocytes can occur and may cause Hold of Clinical Studies with Retroviral Gene Transfer Page 4 possibly life-threatening complications. If allogeneic donor lymphocytes are used into which a drug-inducible cell-killing gene ("suicide gene"; thymidin kinase gene of the Herpes simplex virus) was transferred by a retroviral vector, these cells can be killed in vivo by administration of the specific drug Ganciclovir in the event of a severe GvHD. This treatment therefore helps to avoid life-threatening complications.

Status: 4 registered studies; on hold,
two studies are recommended for continuation with restrictions (modifications of the protocols).

3. HIV gene therapy:
The transfer of lymphocytes which harbour an HIV inhibiting gene serves to suppress HIV replication in vivo.

Status: 1 registered study withdrawn after clinical hold;
1 revised new application, submitted and to be discussed according to the regular procedure.

4. Local gene therapy of rheumatoid arthritis:
(Synovial) cells are removed from the joints affected by arthritis. After retroviral transfer of a gene (IRAP, "interleukin receptor antagonist"), the product of which can block factors contributing to the inflammation of the joint (cytokines), the modified cells are retransferred to the joint. During subsequent surgical removal of the joint, which has so far been unavoidable in this patient group, the cells are removed again.

Status: 1 registered study, on hold;
new application for the continuation of this study submitted; to be discussed according to the regular procedure.

If you need additional information, please contact Dr. Susanne Stöcker (: +49/6103 / 77 1030 or fax: +49/6103 / 77 1262

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Gene Therapy Dose Reduction To Be Considered By Cmte, Feb 26, 2003

Retroviral Gene Therapy Dose Reduction To Be Considered By Cmte.

Retroviral vector dose reduction in gene therapy will be considered by FDA's Biological Response Modifiers Advisory Committee on Feb. 28 as a condition for resuming clinical trials. "The total number of vector integration events will likely increase" with changes in transduction protocols for ex vivo-modified cells and increasingly more efficient vectors, FDA noted in briefing materials for the committee. "One approach to modulate this effect would be to reduce the dose of vector used for transduction" or the cell dose, the agency said. At the meeting, FDA will ask the committee whether current requirements for clinical trials using retroviral vectors to transduce CD34+ hematopoietic stem cells for treatment of Severe Combined Immune Disease (SCID)

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Dream Unmet 50 Years After DNA Milestone Gene Therapy Debacle Casts Pall on Field

By Rick Weiss Washington Post Staff Writer Friday, February 28, 2003; Page A01

It was just the kind of success that scientists had been promising for decades. The boys had been born with faulty versions of a key immune-system gene, leaving them so vulnerable to everyday infections that a common cold could prove fatal. But when French researchers inserted normal copies of that gene into the boys' blood cells, the children were instantly cured -- able to play with their friends instead of living inside sterile bubbles, and ready to go down in history as the first humans to be cured of a disease by gene therapy. Now scientists are scrambling to understand why, in some of the boys, the treatment has triggered a life-threatening form of leukemia, in which their renovated white blood cells are multiplying out of control and the boys are having to undergo chemotherapy to kill the very cells they had so desperately needed. The problem has brought dozens of gene therapy studies to a halt and has cast a pall over the struggling research field, which seeks to cure diseases by giving people new genes.

In an awkward coincidence, the unfolding debacle will be the highlight of a Food and Drug Administration meeting today, 50 years to the day after James Watson and Francis Crick launched the modern age of genetic medicine by deducing, with the help of a cardboard model, the three-dimensional structure of DNA.

Researchers say they have begun to figure out what went wrong in the French experiment. But more generally, experts said, the setback is representative of what is sure to be a difficult adolescence for gene-based medicine, and especially for gene therapy -- the archetypal clinical application of Watson and Crick's celebrated discovery. To be sure, recent advances in genetics promise great improvements in the diagnosis and treatment of diseases. And genetics has already made big differences in forensics and criminal justice, and by giving birth to the burgeoning biotechnology industry. The entire field is to be feted at a series of events in New York, Washington and Cambridge, England -- where Watson and Crick did their seminal work -- between now and April 25, the 50th anniversary of the publication of their results in the journal Nature.

But genes, it is turning out, are not the simple, modular cassettes that scientists had envisioned in the early years. They not only act, but they also listen and react, and they misbehave in the absence of proper oversight and regulation. Scientists, having figured out at last how to give people new genes and turn those genes on, now face the even more daunting challenge of learning how to turn them off -- or at least get them to respond as naturally as possible to the many biochemical signals that normally keep the body in balance.

"For the first eight or nine years of gene therapy, when gene delivery wasn't efficient enough to get an effect, we also didn't see side effects," said W. French Anderson, director of gene therapy at the University of Southern California, and the scientist who led the first U.S. gene therapy experiment in 1990. "But every powerful technology has powerful side effects," Anderson said. "Now we're getting efficient enough to get therapeutic effects, so naturally there's going to be side effects." YYYZSpectacular Results

The French experiment, under the direction of Alain Fischer at the Necker Hospital in Paris, involved children with X-linked severe combined immune deficiency (X-SCID). The disease is generally fatal within the first few years of life, and the only conventional treatment -- a well-matched bone marrow transplant -- is dangerous, results in an imperfect cure and is often unavailable.

Fischer's approach was to remove some of the boys' faulty white blood cells and mix them in laboratory dishes with viruses that had been genetically engineered to contain the gene the boys lacked. The viruses infected the boys' cells, delivering the new genes to the cells' DNA. Then doctors infused the repaired cells into the young patients, who ranged in age from 1 month to 12 months.

The results were spectacular: Nine of the 11 boys were apparently cured. But in September, about three years after treatment, rampant overgrowth of white blood cells was diagnosed in one of the boys. Molecular analyses showed that some of the viruses had dropped their therapeutic payloads in a bad location: atop another gene, called LMO2, which when disrupted can lead to untrammeled cell division and cancer.

At first, scientists hoped the incident was but a bit of bad luck. But in January the same problem was diagnosed in a second boy in the study. And earlier this month the French team announced that tests on a third boy's cells show the same molecular disruption, though the boy has not developed symptoms. Now Fischer and others have come to believe that most of the boys treated with the gene-laden viruses will be found to have the same problem. The odds of a virus dumping its load on LMO2 are less than one in 100,000 per cell, but as many as 150 million cells are infected and infused into the young patients, said Christof von Kalle of Cincinnati Children's Hospital Research Foundation, who is conducting much of the analysis for the French team.

It is still uncertain whether LMO2 disruption by itself is enough to trigger leukemia, von Kalle and Fischer said in interviews, or whether additional disruptions are needed to start that process. Also unclear is whether such disruptions may pose a medical risk in only the youngest of patients, whose immune systems are still in a rapid stage of development. The two boys in which leukemia was diagnosed so far were the youngest treated, at 1 month and 3 months of age. Nonetheless, several experts said, the incident indicates the kind of problems the field is sure to see more of now that scientists have finally begun to overcome what had been their main problems: an inability to get enough new genes into cells to make a difference, and an inability to get those new genes to work. "Up until now, gene therapy was always looked at as an efficiency problem, with not enough cells expressing the gene," von Kalle said. "Now for the first time we've fallen off the horse on the other side." Suspended Studies For the FDA, the most pressing problem is to figure out the extent to which similar experiments might harbor the same risks. The agency has suspended 30 U.S. gene therapy experiments that were using or were about to use genes or viruses similar to those in the French study. Patients in those studies are now being told of the newly discovered risk, and researchers have been instructed to beef up their surveillance for untoward effects.

Today's meeting will focus largely on the question of which experiments should be allowed to move forward once added safety measures are put into place. It may be, for example, that the leukemia risk is significant only when the experiment involves the X-SCID gene -- whose biological purpose, after all, is to help white blood cells proliferate. In that case, similar experiments involving different genes to cure different diseases may get the go-ahead. But, scientists said, gene therapy is going to have to do better at mimicking the body's own complicated means of regulating genes, in terms of when and where in the body they become active and just how active they ought to be.

One goal for the field is to wean itself from the retroviruses that were used in the French experiment. The viruses have been popular because they insert their genetic payloads directly into cells' DNA, giving the newly delivered genes a platform from which they can work indefinitely.

But retroviruses splice those genes at random locations in a cell's DNA, and as the French study shows, some locations are worse than others. Researchers have begun to experiment with other gene-delivery vehicles, including other kinds of viruses, synthetic fat bubbles, and even "naked DNA" that can sometimes find its way into cells without any help. Researchers are also developing gene therapies that include so-called suicide genes, which would allow doctors to shut down the added gene by giving a patient a special drug. And they are developing genetic inserts that include not only the therapeutic gene itself, but also the flanking genetic sequences that help the gene respond to the body's own signals to turn on or off as needed.

"There are almost as many gene therapies as there are diseases to be cured," Fischer said. "The problems to be solved, efficacy and toxicity, are potentially extremely different for each." The ultimate goal is "homologous recombination," a method by which unhealthy genes are removed from the body's cells and healthy replacements -- along with proper regulatory elements -- are inserted precisely in their places. Earlier this year, scientists at the University of Wisconsin reported the first successful homologous recombination in laboratory-grown human stem cells, a first step in the difficult process of making the technology work for patients. "We are far from using that at the clinical level," Fischer said. "In the long term, we can all work on making that dream real."

More generally, scientists said, the lesson to be gleaned from the French experiment is that, practically speaking, even the best genetic therapies will be subject to the same frustrating truth that has long dogged conventional medicine: Biology is complicated, and any amount of tinkering is bound to bring surprises. Despite all the promises of a perfect new medicine -- of treating diseases at their molecular cores and building healthy bodies from the inside out -- even the best genetic therapies will still force doctors and patients to balance benefits against risks. Indeed, said Philip Noguchi of the FDA division that oversees gene therapy, it may even be that with minor modifications the French treatment for X-SCID will be deemed acceptable to regulators and parents, even with its risks.

"What we have here is a difficult disease for which you have extraordinarily promising results, kids leaving the hospital and leading relatively normal lives, and you also have adverse events which are serious but which so far appear to be treatable with chemotherapy," Noguchi said. That is not the perfect future that Watson and Crick envisioned when, after making their historic discovery on Feb. 28, 1953, they repaired to the nearby Eagle pub and Crick made his now famous declaration: "We've discovered the secret of life!" But it's a future that gives Fischer's boys some hope, which they wouldn't have had a few years ago.

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Erneuter Daempfer fuer die Gentherapie - Der zweite Leukaemie-Fall gibt den Forschern Raetsel auf

Neue Zuercher Zeitung, 29.01.2003

Nach einer Gentherapie an einem Pariser Kinderspital hat inzwischen ein zweites Kind eine Leukaemie-aehnliche Krankheit entwickelt. Die Wissenschafter versuchen jetzt zu klaeren, ob das Risiko einer solchen Erkrankung Protokoll-spezifisch ist oder bei jeder Gentherapie besteht. Letzteres waere wohl das Aus fuer diesen Therapieansatz.


text truncated for copy-right reasons, please read the full text at:


Alain Fischer selbst vermutet, dass das Alter der Patienten zur Zeit der Gentherapie eine Rolle bei der Krebsentstehung gespielt hat. Denn waehrend die Kinder, bei denen die Gentherapie problemlos verlief, zur Zeit der Behandlung zwischen sechs und elf Monate zaehlten, waren die zwei erkrankten Knaben schon im Alter von einem beziehungsweise drei Monaten behandelt worden. In diesem Alter, so vermutet Fischer, koennen die Zellen vielleicht noch Gene aktivieren, die eigentlich nur die Entwicklung des Foetus steuern. In einem spaeteren Entwicklungsstadium wuerden die Produkte dieser Gene moeglicherweise zur Entartung der Zellen fuehren.

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LE MONDE | 16.01.03 | 14h00

Un deuxième cas de leucémie a été diagnostiqué chez un enfant français soigné par thérapie génique
Les autorités sanitaires américaines ont à leur tour décidé de suspendre ce type d'essais cliniques.

Douze enfants souffrant d'une maladie héréditaire avaient été traités à l'hôpital Necker à Paris.

L'agence française de sécurité sanitaire des produits de santé (Afssaps) a annoncé, mercredi 15 janvier, qu'un deuxième cas d'une forme de leucémie avait été "très récemment" identifié chez un enfant atteint d'une affection héréditaire et qui avait été soigné, avec un apparent succès, grâce à une thérapie génique originale mise au point à l'hôpital Necker- Enfants Malades à Paris. Ce traitement expérimental, développé par une équipe de scientifiques et de médecins dirigée par les professeurs Marina Cavazzana-Calvo et Alain Fischer, était il y a peu encore considéré comme l'un des meilleurs espoirs de cette nouvelle branche de la médecine qui consiste à introduire dans le génome des malades un gène capable de pallier le dysfonctionnement génétique à l'origine de la maladie.

Depuis 1999, douze enfants souffrant d'un " déficit immunitaire combiné sévère" (affection imposant une hospitalisation en milieu stérile et pouvant, dans certains cas, être soignée par une greffe de moelle osseuse) avaient été pris en charge par cette équipe de réputation internationale. Chez la plupart d'entre eux, une correction de l'anomalie d'origine génétique avait pu être obtenue.

La découverte, en septembre 2002, d'une forme de leucémie chez l'un des sept enfants avait conduit à la suspension de cet essai clinique ainsi que celle de nombreux autres essais de thérapie génique à travers le monde (Le Monde du 5 et du 18 octobre 2002). Une enquête avait alors été lancée, visant notamment à établir s'il y avait un lien de causalité entre la leucémie et la thérapie génique. De nombreux éléments plaidaient en faveur de l'existence d'un tel lien, mais le doute pouvait encore subsister.


La survenue d'une deuxième complication similaire pèse aujourd'hui très largement en faveur d'une telle hypothèse. Pour les spécialistes, le scénario le plus vraisemblable est que l'insertion du gène via un vecteur rétroviral dans des cellules souches de la moelle osseuse a, chez les deux enfants, induit une prolifération maligne d'un certain type de cellules du système immunitaire. Les deux enfants sont actuellement soignés par chimiothérapie et les familles des autres jeunes patients ont été informées du risque potentiel auquel ces derniers étaient exposés.

Comme dans le cas précédent, une enquête scientifique va être menée pour tenter de mieux comprendre l'origine exacte de l'accident afin de développer à l'avenir des protocoles de thérapie génique capables de prévenir ce risque. Pour leur part, informés par leurs homologues français, les responsables sanitaires américains ont annoncé, dès le mardi 14 janvier, l'interruption d'une trentaine d'essais cliniques de thérapie génique actuellement en cours outre-Atlantique. Ces essais concernent pour l'essentiel des personnes atteintes du sida ou souffrant de cancer.

La Food and Drug Administration (FDA) a précisé qu'elle avait pris cette décision par mesure de précaution et que les essais concernés étaient ceux qui, comme l'essai parisien, avaient recours à des gènes portés par des vecteurs rétroviraux introduits dans des cellules souches du sang. La FDA ajoute que cette mesure est temporaire et qu'aucun accident du type de ceux observés en France n'a été constaté aux Etats-Unis.

Parce qu'elle conduit à faire une nouvelle analyse du rapport bénéfice-risque d'un des très rares essais de thérapie génique au monde qui avait démontré une réelle efficacité, la situation française soulève une vive inquiétude. Celle-ci est bien évidemment ressentie dans les milieux scientifiques concernés et plus encore auprès des autorités sanitaires sous l'égide desquelles ces essais cliniques sont conduits.

" Il ne fait aucun doute que les essais de thérapie génique comportant l'usage de rétrovirus dans les cellules souches doivent, malheureusement, être arrêtés, a déclaré au Monde le professeur David Klatzmann (groupe hospitalier Pitié-Salpêtrière, Paris) président de la société européenne de thérapie génique. Pour autant, la situation actuelle ne remet nullement en question la poursuite des autres expériences qui n'utilisent pas cette méthodologie. Nous devons désormais nous attacher à comprendre comment de tels accidents ont pu survenir."

Jean-Yves Nau

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Un petit français, parmi les neuf guéris par un «gène médicament», souffre d'une leucémie
Thérapie génique : un deuxième enfant victime d'une complication

Le Figaro, 16.1.03; Catherine Petitnicolas [16 janvier 2003]

Un deuxième petit enfant traité jusqu'ici avec succès par thérapie génique (qui consiste à introduire un gène médicament dans le noyau des cellules) pour un déficit immunitaire sévère (1) a développé une maladie proche de la leucémie, a confirmé hier l'Agence française de sécurité sanitaire des produits de santé (Afssaps). Le bambin, âgé de trois ans, a heureusement bien répondu à la chimiothérapie mise en oeuvre dès la découverte de cette leucémie, peu de temps avant Noël.

Mais l'annonce de la survenue d'un deuxième cas de complication parmi ces dix «bébés bulles» traités et neuf jusqu'ici guéris grâce à une thérapie génique innovante mise en oeuvre dès 1999 par l'équipe du Pr Alain Fischer et Marina Cavazzana-Calvo à l'hôpital Necker à Paris jette un grand trouble dans la communauté scientifique, et bien évidemment chez les parents. Les autorités sanitaires américaines ont suspendu, dès mardi, une trentaine d'essais de thérapie génique utilisant des vecteurs similaires (des rétrovirus servent à transporter le gène médicament) utilisés pour traiter des maladies sanguines liées à des anomalies des cellules souches de la moelle osseuse.

Dès l'annonce du premier cas de complication en octobre dernier (2), l'équipe française avait sur-le-champ décidé d'interrompre tous ses essais de thérapie génique et de surveiller très attentivement tant sur le plan clinique que biologique les huit autres enfants ayant reçu depuis trois ans un traitement similaire. Cela a permis de déceler très vite la survenue de cette deuxième complication chez un petit garçon quelques jours avant Noël. «Nous avons aussitôt prévenu les autorités réglementaires françaises et internationales qui se sont engagées à ne délivrer l'information au public qu'à partir du 29 janvier, prochain le temps de nous laisser avertir calmement et humainement toutes les familles concernées», explique le Pr Fischer. «Mais, contre notre volonté, les Américains ont décidé de rendre publiques plus tôt que prévu ces nouvelles données, ce qui ne nous a pas laissé le temps de donner l'information en toute sérénité aux familles. Une attitude qui nous semble moralement condamnable», tempête le médecin, dont la grande rigueur scientifique et l'honnêteté intellectuelle ont toujours été saluées par ses pairs. Ce qui n'a pas été le cas chez certains initiateurs de thérapie génique américains qui ont volontairement «omis» de faire état de graves complications.

«La prudence nous impose bien évidemment d'interrompre notre essai, de réfléchir sur l'ensemble de la stratégie adoptée, de comprendre et d'analyser les mécanismes à l'origine de ces complications mais en aucun cas cela ne condamne l'approche de la thérapie génique, souligne-t-il avec force. Ces complications, aussi douloureuses soient-elles, font malheureusement partie des aléas de toute recherche médicale.» Pour expliquer l'apparition de ces «leucémies», les hypothèses ne manquent pas, qu'elles soient liées au très jeune âge des deux petits patients, à la maladie initiale, ou au vecteur rétroviral lui-même. Mais une chose est sûre, ce deuxième cas de complication illustre aussi les limites de l'expérimentation animale, qui, si longue soit-elle, n'avait jamais permis de mettre à jour un tel risque.

Même analyse du côté d'Olivier Danos, spécialiste des vecteurs rétroviraux au CNRS et directeur scientifique du Genethon. «C'est un grand pas en arrière certes mais il ne faut pas être défaitiste. L'histoire de la recherche en médecine est émaillée d'accidents et de complications qui permettent aussi d'apprendre une quantité de données nouvelles. Il faudra reconsidérer notre approche et remettre la priorité sur les recherches concernant le ciblage du gène transporté au coeur du génome.» Car, jusqu'ici, si les vecteurs utilisant des rétrovirus pour véhiculer les gènes médicaments sont les seuls capables de s'insérer dans le génome du noyau des cellules, on ne sait pas très bien à quel niveau ils le font. Avec le risque de provoquer une mutagenèse insertionnelle, en clair d'activer un gène à l'origine d'une prolifération anarchique des cellules, donc d'un cancer. Un risque connu et redouté depuis longtemps par les chercheurs et qui semble aujourd'hui malheureusement prendre corps.

Si certains penchent pour un moratoire, l'AFM, l'Association française contre les myopathies, qui finance ces essais depuis plus de dix ans renouvelle sa confiance à l'équipe de Necker et va soutenir des travaux portant sur des transporteurs de gènes plus performants utilisés dans de prochains essais sur les déficits immunitaires.

(1) Il s'agit d'un déficit immunitaire combiné sévère lié au chromosome X, maladie héréditaire extrêmement rare (cinq cas par an en France) qui ne touche que les garçons.

(2) Nos éditions du 4 octobre 2002.

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Par mesure de sécurité, l'autorité sanitaire américaine stoppe plusieurs études faisant appel à un type particulier de virus.

l'Agefi, 16.01.2003

La thérapie génique subit les foudres de la FDA. L'institut soupçonne les rétrovirus d'être à l'origine de deux cas de leucémie déclarés chez des «enfants bulles" traités en France.

Boudé par les médias faute de succés grandiloquents, le domaine émergent de la thérapie génique revient sur le devant de la scène. Un retour malheureusement porteur de mauvais présages. Mercredi, la Food and Drug Administration (FDA) américaine a fait savoir qu'elle suspendrait outre-Atlantique plusieurs études de thérapie génique utilisant un type particulier de virus, les rétrovirus, pour insérer des génes répaateurs chez les patients.

Cette mesure survient trois mois aprés la décision du professeur Alain Fischer de l'Hôpital Neck er à Paris de suspendre l'essai clinique de thérapie génique qu'il menait avec succès depuis trois ans pour guérir des «enfants bulles", décision qui avait été motivée par la survenue d'une forme de leucémie chez l'un des huit enfants traités. A cette époque, la FDA avait déjà pris certaines précautions, en interdisant outre-Atlantique trois études similaires à celle du groupe de chercheurs français. Depuis, un nouveau cas de leucémie a été déclaré parmi les onze patients que comptabilise désormais l'étude.

Le domaine émergent de la thérapie génique n'en est pas à son premier coup dur. Le décès, en 1999, d'un adolescent américain pendant qu'il participait à un essai clinique de phase I, avait déjà fait de l'ombre à une technologie qui n'en était alors quà ses balbutiements. Trente essais sur deux cents sont concernés L'autorité sanitaire américaine n'a pas donné de précisions sur les essais et sociétés touchés par cette sanction. Plusieurs entreprises de génétique notamment Avigen, Vical, CenVec et Cell Genesys, ont déclaré à l'agence Bloomberg ne pas faire appel dans leurs recherches aux rétrovirus mis en cause. De l'avis de Philip Noguchi, dirigeant de la division de la FDA en charge du domaine de la thérapie génique, environ trente études sur les deux cents actuellement menées aux Etats-Unis sont concernées.

Agir au coeur méme des gènes

Très controversée, l'approche de la thérapie génique est pourtant extremement fine et élégante: des génes ou des fragments de géne sont directement utilisés comme médicament, afin de suppléer ou de réparer un géne défectueux. Un virus désactivé assure le transport de ces gènes dit «thérapeutiques" (aussi appelés «transgènes" dans le jargon scientifique) au coeur de nos gènes.

Dans le cas particulier des «enfants bulles», qui souffrent d'un déficit immunitaire combiné sévère lié à une anomalie génétique sur le chromosome X (DICS-X), la thérapie génique avait pour but d'offrir une alternative aux greffes de moelle, seul moyen jusqu'alors disponible pour soigner cette maladie rare. Son principe consiste à infecter les cellules possédant une version anormale du géne au moyen d'un cétrovirus porteur de la bonne version du gène. Ce gène réparateur va s'insérer au hasard dans le génome du patient. C'est précisément cette insertion aléatoire que l'on soupconne être à l'origine des complications sévères dont sont victimes les «enfants bulles". Si celle-ci se fait à proximité d'un oncogéne (géne qui peut engendrer un cancer), elle peut entrainer la mutation de ce dernier et le développement de cellules malignes.

Evaluer le rapport risque/bénéfice

Les deux cas de leucémie sont-ils le résultat d'une coincidence rare ou d'un danger bien réel? De nombreuses recherches se ront encore nécessaires pour répondre à cette question. Pour l'heure, l'équipe d'Alain Fischer étudie les caractéristiques des sites d'intégration des génes réparateurs. Le but à terme étant de pouvoir évaluer les risques qu'un tel accident survienne. Au vu de l'extrême gravité de la maladie, se posera alors la question du ratio risque/bénéfice acceptable en la matière.

La FDA prétére pour sa part opter pour la prudence et suspendre toutes les études de thérapie génique faisant appel au même type de virus (rétrovirus) que le laboratoire français, ceci indépendamment de la maladie traitée. Selon les données du National Institute of Health (NIH) américain, le rétrovirus est utilisé pour tenter de soigner de nombreuses maladies, notamment le cancer du sein, les mélanomes, les maladies du foie ou encore le sida. Un comité d'experts doit se réunir en février prochain afin de discuter des conséquences des résultats obtenus par l'équipe parisienne.

La FDA pourrait revenir sur sa décision La décision de la FDA n'est toutefois pas irréversible. Les demandes de reprise d'études seront étudiées cas par cas, en fonction de la sévérité de la maladie, des risques de complications graves et des bénéfices potentiels du traitement.

Manuela Palma de Figueiredo

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Eine medizinische Lotterie? Zweiter Leukaemiefall verunsichert allerorten die Gentherapeuten

Frankfurter Allgemeine Zeitung, 17.01.2003, Seite ,

Die Gentherapie hat, wie gestern kurz gemeldet, durch das Auftreten eines zweiten Leukaemiefalls bei einem der behandelten Patienten einen schweren Rueckschlag hinzunehmen. Die Verunsicherung bei den Medizinern ist greifbar, in Deutschland beraten die Fachleute ueber die Fortsetzung klinischer Studien, und in den Vereinigten Staaten hat die Food and Drug Administration, die zustaendige Genehmigungsbehoerde, umgehend 27 Therapieversuche mit mehreren hundert Patienten ausgesetzt.

Der Arzt und Forscher Alain Fischer vom Kinderkrankenhaus Necker in Paris hatte in den vergangenen Jahren ein knappes Dutzend Kinder, die an einer lebensbedrohlichen angeborenen Immunschwaeche litten, mit einer Gentherapie behandelt, um den Erbfehler auszugleichen. Die Therapie schien zunaechst außerordentlich erfolgreich zu sein, denn sie verhalf den Kindern zu einem robusten Abwehrsystem. Einige Kinder wurden sogar als geheilt angesehen. Die frueher von Infektionen bedrohten Patienten konnten alsbald ein ganz normales leben fuehren.

Im vergangenen Sommer, knapp drei Jahre nach der Gentherapie, kam es jedoch bei einem der Patienten zu einer Wucherung bestimmter Abwehrzellen, sogenannter T-Lymphozyten. Diesen Fall konnten die Forscher noch als ein zufaelliges, aeußerst seltenes Ereignis interpretieren. Daß nun bei einem zweiten der insgesamt elf gentherapierten Kinder eine Leukaemie auftrat, scheint, wie Klaus Cichutek, Vizepraesident des Paul-Ehrlich- Instituts in Langen, sagte, jedoch darauf hinzuweisen, daß die Therapie an sich ein vergleichsweise hohes Leukaemierisiko in sich birgt. Diesen zweiten Leukaemiefall gab Fischer seinen Kollegen bereits am 20. Dezember 2002 bekannt, jedoch mit der Bitte, die Information zunaechst nicht an die Aeffentlichkeit zu tragen, bis die Eltern aller behandelten Kinder benachrichtigt worden seien. Er wollte verhindern, daß diese den Zwischenfall aus der Presse erfuhren, und nahm dafuer eine gewisse, durch die Feiertage verlaengerte Verzoegerung des Informationstransfers in Kauf.

Worauf das Leukaemierisiko letztlich beruht, ist noch nicht geklaert. Die Forscher haben jedoch durch die genaue Gen-Analyse der Immunzellen vor allem des ersten Patienten bereits mehrere Hinweise gewonnen, wie die Blutzellwucherungen entstanden sein koennten. Zum Einschleusen des therapeutischen Gens in Blutstammzellen der Patienten verwendeten die Wissenschaftler sogenannte retrovirale Vektoren, Gentransporter, die sich von Retroviren ableiten. Diese Genkonstrukte bauen sich im Zellkern in eines der Chromosomen ein und verankern dabei auch das therapeutische Gen dauerhaft im Genom. Es ist den Forschern schon lange bekannt, daß sich der retrovirale Vektor zufaellig auch inmitten eines funktionell wichtigen Gens niederlassen und das gesunde Verhalten dieser Zelle dadurch stoeren kann. Es war theoretisch auch zu befuerchten, daß der Gentransporter in seltenen Faellen ein an der Zellteilungskontrolle beteiligtes Gen zerstoeren und damit Zellwucherungen beguenstigen koennte. Da aber in der Regel mehr als ein halbes Dutzend Kontrollstationen der Zellteilungsmaschinerie ausfallen muessen, bevor aus einer gesunden Zelle eine Krebszelle wird, hielten die Forscher das Entartungsrisiko insgesamt fuer eher gering.

Die molekulargenetische Analyse der Blutkrebszellen des ersten Patienten sowie das Auftreten des zweiten Leukaemiefalls hat nun die Hypothese aufgeworfen, daß der retrovirale Vektor in Kombination mit dem spezifischen uebertragenen Gen mit einem besonders hohen Leukaemierisiko einhergeht. Bei dem ersten Patienten hat sich gezeigt, daß sich der Gentransporter zufaellig in einem Gen niederließ, das fuer die Vermehrung und Reifung der verschiedenen Blutzellen wichtig ist. Das sogenannte Imo2-Gen war bei dem Patienten ueberaktiv geworden und wirkte nun wie ein krebsfoerderndes Gen, ein Onkogen. Diese Interpretation stimmt mit der Beobachtung ueberein, daß man bei bestimmten Formen von Leukaemien gelegentlich eine unerlaubte Aktivierung des lmo2-Gens (auf der Basis einer Translokation) gefunden hat.

Weiter erhoeht wurde das Krebsrisiko im vorliegenden Fall jedoch oftenbar durch das therapeutische Gen selbst. Hierbei handelt es sich um die Erbanlage fuer eine Komponente eines Rezeptors von Immunzellen. Dieser stellt ein Glied in einer laengeren Signalkette fuer die Teilungskontrolle der Zellen dar. Daß die beiden Kinder erst etwa drei Jahre nach der Therapie an Leukaemie erkrankten, laeßt sich als ein Hinweis deuten, daß sich in den T-Zellen, die durch rege Teilung aus den Blutstammzellen entstanden, zwischenzeitlich weitere genetische Defekte einschlichen. Auf diese Weise wurde die vielfach abgesicherte Zellteilungskontrolle schließlich durchbrochen. und es entwickelte sich eine Leukaemie.

Die zahlreichen anderen Gentherapien mit retroviralen Vektoren, die derzeit weltweit entwickelt werden, verwenden als therapeutisches Gen voellig andere Erbanlagen. Sie befinden sich auch erst in einer fruehen Phase der klinischen Erprobung. Bislang gibt es keine Hinweise, daß auch bei einer dieser Gentherapien das Krebsrisiko erhoeht waere. Gentherapien, die sich derzeit in Deutschland in der Erprobung befinden beziehungsweise beantragt sind, betreffen die Behandlung der Spender-gegen-Wirt-Krankheit, der als chronische Granulomatose bezeichneten Abwehrschwaeche sowie die Therapie von HIV-Infektionen und rheumatischer Arthritis. Die in diesen Studien verwendeten Gene besitzen kein wachstumsfoerderndes Potential. Doch angesichts der Verunsicherung, die der zweite Leukaemiefall ausloeste, wollen die Experten der Bundesaerztekammer gemeinsam mit dem Paul-Ehrlich-Institut nun das weitere Vorgehen bei Gentherapien neu ueberdenken. Eine vorrangige Aufgabe duerfte außerdem darin bestehen, nach besseren und gleichzeitig effektiven Gentransportern zu suchen.



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FDA News, Vol. 4, No. 11Thursday, Jan. 16, 2003


The FDA has temporarily suspended 27 U.S. gene-therapy trials after a second child in France contracted a leukemia-like illness sparked by a gene-therapy treatment. None of the hundreds of patients in the American trials reported similar illnesses, but the FDA said it is suspending the trials as a precaution. This will bring to 30 the total number of U.S. gene-therapy trials halted as a result of illnesses reported in European trials.

The National Institutes of Health's Recombinant DNA Advisory Committee will discuss the clinical hold later this month. The FDA's Biological Response Modifiers Advisory Committee will discuss the matter Feb. 28. To see the FDA's announcement of the trial suspension, go to


FDA TALKS, jan 16, 2003


Agency Action Provides Way for Patients to Continue Therapy Under Certain Circumstances if Additional Measures Taken

In a precautionary measure, the Food and Drug Administration (FDA) today placed on "clinical hold" all active gene therapy trials using retroviral vectors to insert genes into blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial has developed a leukemia-like condition. Both this child, and another who had developed a similar condition last August, had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome."

Infants with X-SCID have a gene defect that leads to a complete lack of white blood cells that can fight infection. Without treatment, they die from complications of infectious diseases during the first year of life. The only treatment for this condition is a bone marrow transplant.

In early results of the French study in which a normal gene is inserted into blood stem cells of patients with X-SCID, nine of the 11 children had promising results and could leave the hospital and lead relatively normal lives. After notification of the first case last year, FDA identified the three U.S. gene therapy studies that most closely resembled the French trial and stopped enrollment of human subjects in those trials. They remain on clinical hold, a condition which FDA can impose when adverse events or other safety questions arise during a clinical study.

FDA's continuing review of adverse event reports from all U.S. studies involving retroviral vectors has to date found no evidence of leukemia caused by the gene therapy. Moreover, the agency has to consider the potential risks of any experimental therapy within the context of the disease it may treat - in this case a devastating disease in children. FDA's action includes a temporary hold on the enrollment of new patients in a subset of gene therapy trials that involve the use of retroviruses to insert new genes in blood stem cells, irrespective of the disease condition.

The temporary hold reflects FDA's appreciation that some of these trials involve patient populations and gene therapy products that may be appropriate to continue after they are updated to reflect this new risk information. FDA will consider and evaluate specific requests for clinical indications for fatal or life-threatening disorders for which there are no viable alternative treatments. In all cases, sponsors will need to inform treated and new subjects of the two adverse events, and will need to have a plan to actively monitor subjects for leukemia like events.

FDA continues to review the data from the adverse event in France, as well as the risks and potential benefits of all ongoing gene therapy trials, and will continue to work closely with the National Institute of Health's Office of Biotechnology Activities to oversee gene therapy studies in the U.S. The agency expects to hold an advisory committee meeting late next month to discuss the new adverse event in particular and retroviral gene therapy in general.


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Second Boy Receiving Gene Therapy Develops Cancer FDA Responds to Event in France by Suspending 27 U.S. Studies Involving Similar Techniques

By Rick Weiss Washington Post Staff Writer Wednesday, January 15, 2003; Page A09

For the second time in four months, a child treated with an experimental gene therapy in France has developed a form of leukemia apparently caused by the treatment.The new cancer case, in a boy who was given new genes to cure a severe immune system deficiency, undercuts scientists' initial hopes that the first case was a fluke, and calls into question the value of the radical treatment, which had been promoted as the first successful use of DNA to cure a disease.

In response, the Food and Drug Administration yesterday suspended as "a precautionary measure" more than two dozen U.S. gene therapy studies that involve techniques similar to those in the French experiment. Three U.S. gene therapy studies that even more closely resemble the French experiment had already been on hold since the first leukemia case came to light in September.

The new cancer case is a serious blow for an experimental field that has struggled for a dozen years to produce its first cure and which suffered a terrible setback in 1999 with the death of an American patient, Arizona teenager Jesse Gelsinger. The approach involves the delivery of new genes to take over for missing or broken ones.Gelsinger died in a gene therapy experiment at the University of Pennsylvania that was later heavily criticized by the FDA for violating basic safety rules. But until the recent leukemia cases, gene therapy had at least seemed safe when used in accordance with approved protocols. Now, scientists said, that sense of safety has been undermined.

"When the first leukemia showed up, we as a community were certainly upset and concerned about the patient," said Joe Glorioso, president of the American Society of Gene Therapy and chairman of molecular genetics and biochemistry at the University of Pittsburgh Medical Center. "But when the second event happened, that really is a red flag."Nonetheless, Glorioso and others noted, no cases of leukemia have been documented in any of the thousands of other people who have received some form of gene therapy, which suggests that the risk may be specific to this particular disease or treatment plan. Researchers said they held out hope that they will learn how to modify the treatment so it can still be used in children born with the boys' life-threatening disorder -- severe combined immunodeficiency, or SCID. Affected children can die from even minor infections, and the only cure -- a bone marrow transplant from a well-matched donor -- is unavailable for many."We continue to see gene therapy as a promising therapy for all those who have not benefited from current technologies," said Philip Noguchi, acting director of the FDA's office of cellular, tissue and gene therapies, which regulates gene therapy experiments in this country.

Noguchi praised the leader of the French study, Alain Fischer of the Necker Hospital in Paris, for promptly informing the FDA about the new leukemia case last month. The setback became public yesterday when the FDA placed a "clinical hold" on all U.S. gene therapy experiments that, like the French experiment, use retroviruses to deliver new genes into blood stem cells. The FDA hold demands that studies already underway be stopped and enrollment of new patients be suspended.Noguchi estimated that 27 such trials have been approved in this country and are at various stages of patient enrollment or testing. The agency will assess the latest data at a Feb. 28 meeting, he said, but it may lift the hold on some studies before then if it believes patients are more likely to be harmed by the shutdown of a study.Few details about the new case were available yesterday. The boy was one of about 11 children treated by Fischer in the past several years, nine of whom Fischer has said appear to be cured of their immune system disease. The treatment uses retroviruses to deliver a crucial immune system gene to blood cells.

Glorioso said yesterday he had been told that the latest leukemia case involved a boy who was admitted to a hospital in Louisiana, suggesting he may be an American who was treated in Paris.In both leukemia cases, tests showed that the cancer was apparently triggered when the newly delivered gene disrupted a nearby gene whose job is to help prevent cancer.Both boys have been treated for their leukemia and are "stable," Noguchi said.

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FDA halts gene therapy studies

By Associated Press, 1/15/2003

WASHINGTON - A second European toddler apparently suffered a leukemia-like side effect from gene therapy that cured him of the rare but deadly ''bubble boy disease,'' prompting US officials to suspend 27 more gene therapy studies yesterday while they investigate the risk.

Bubble boy disease - an immune disorder formally called severe combined immunodeficiency, or SCID - is the only disease ever to be cured with gene therapy.But three months ago, a boy whose life was saved by a SCID gene therapy experiment in France when he was a baby became ill with a leukemia-like syndrome at age 3.Scientists have long warned that cancer is a possible risk from any gene therapy that uses retroviruses, a type of virus that permanently invades cells, to deliver new genes into a patient's body. No one else who received gene therapy for SCID or other diseases had ever developed leukemia-like symptoms.

That first sick toddler prompted US and French scientists in October to stop gene therapy experiments for SCID, including three in the United States.But a second toddler in the French SCID experiment has developed a similar leukemia-like side effect, Food and Drug Administration scientists said yesterday.

Quietly notified by French researchers about a month ago, the FDA decided that the second serious side effect warranted a bigger precaution: Temporarily stopping about 27 more US experiments that use retroviruses to insert new genes into blood stem cells in hopes of fighting diseases other than SCID.The FDA did not release a list of the experiments but said it will target diseases such as cancer and include several hundred participants.

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U.S. Halts Gene Therapy Studies Over Risk U.S. Suspends 27 More Gene Therapy Studies After Second Illness From 'Bubble Boy' Treatment

The Associated Press WASHINGTON Jan. 15 &emdash;

U.S. officials are suspending 27 more gene therapy studies while they investigate a possible serious risk: A second European toddler cured of the deadly "bubble boy disease" by gene therapy has come down with an apparent leukemia-like side effect.

It marks the second time in three months that health officials have interrupted gene therapy studies because of the grave side effect.

Bubble boy disease an immune disorder formally called severe combined immunodeficiency, or SCID is the only disease ever to be cured with gene therapy. But three months ago, a boy whose life was saved by a SCID gene therapy experiment in France when he was a baby came down with a leukemia-like syndrome at age 3.Scientists have long warned that cancer is a possible risk from any gene therapy, such as that for SCID, that uses retroviruses, a type of virus that permanently invades cells, to deliver new genes into a patient's body. Still, no one given gene therapy for SCID or other diseases had ever had such a side effect.

That first sick toddler prompted U.S. and French scientists in October to stop gene therapy experiments for SCID, including three in this country.Now a second child in the French SCID experiment has come down with that same leukemia-like side effect, Food and Drug Administration scientists announced Tuesday.

Quietly notified by French researchers about a month ago, the FDA decided that the second serious side effect warranted the more serious response: temporarily stopping about 27 more U.S. experiments that use retroviruses to insert new genes into blood stem cells in hopes of fighting diseases other than SCID.The FDA didn't release a list of the experiments but said they include some targeting such diseases as cancer and include several hundred participants.The FDA said if researchers argue that any of the retrovirus experiments offered a sole option to people with life-threatening illnesses, the agency would work to let them restart on a case-by-case basis, with appropriate warnings to participants.

The three SCID gene therapy experiments, however, remain on hold for at least a few more months while officials investigate the second side effect, FDA officials said."We do think it's a prudent course," because "there are things going on here that we really don't understand," FDA gene therapy chief Dr. Phil Noguchi said. The FDA will convene its scientific advisers next month to pore over the research and debate future steps.

"It's very unfortunate that with the first real success in a very difficult disease, that there's this downside," said American Society for Gene Therapy president Joe Glorioso, a University of Pittsburgh geneticist. Without the gene therapy, these two boys almost certainly would have died of their SCID because they had no other treatment options, he noted. Yet without the gene therapy, he said, "it's unlikely these patients would have ever developed leukemia."

Both boys responded well to chemotherapy and are stable, but their long-term outlook is uncertain, Noguchi said. He released few details about the second patient, including his nationality, other than that he was cured of SCID as a baby and became ill with the cancer-like syndrome almost three years later. SCID babies 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 Paris' Dr. Alain Fischer generated great excitement when his gene therapy apparently cured nine of the 11 boys he treated who had the most severe SCID-type, called X-SCID. He drew bone marrow from the boys, culled immune cell-creating stem cells from it, and mixed in a virus containing the gene their bodies lacked. Injected back into their bodies, the stem cells worked properly.

On the Net: FDA announcement:

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More Gene Therapy Trials Halted


January 15, 2003

The Food and Drug Administration suspended another 27 gene therapy trials yesterday - half of those under way in the United States - after the agency learned that a second French child had developed leukemia after receiving the promising, yet highly experimental, treatment.

The agency had halted three trials last October following the revelation that one child had developed the potentially fatal form of cancer. The suspension was broadened to include an additional 27 trials yesterday "because of unanswered questions about what is going on," said Dr. Philip Noguchi, who is in charge of gene therapy issues at the FDA. But Noguchi cautioned that participants in the programs should not be unduly alarmed because an intensive study has revealed no other cases of leukemia outside the French program.

An emergency meeting has been called for Friday by the Office of Biotechnology Activities at the National Institutes of Health to discuss the problem. The FDA has also scheduled a meeting Feb. 28 at which some of the trials could be reinstated.

The two children who developed leukemia were among 11 infants with a disease, known as X-linked severe combined immune deficiency, treated with gene therapy by Dr. Alain Fischer and his colleagues at the Necker Hospital for Children in Paris. The illness is commonly known as "bubble boy" disease. The children have a defective gene, called GammaC, which prevents them from developing immunity against infectious diseases. Untreated, such children die within the first year of their lives due to severe and recurrent infections.

Fischer used a so-called retrovirus to insert a healthy copy of the gene into the children's hematopoietic (blood-forming) cells. His trial was widely hailed because nine of the 11 children apparently were cured of their disease and were able to go home. But last October, one of the children, now 3 years old, was found to have leukemia.

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30 trials of gene therapy are suspended by FDA Second case of leukemia in similar French study raises questions, alarms

By Thomas H. Maugh II Special To The Sun Originally published January 15, 2003

The Food and Drug Administration suspended 30 gene therapy trials yesterday - half of those under way in the United States - after learning that a second French child had developed leukemia after receiving the promising, yet highly experimental, treatment. The agency had halted three trials in October after the revelation that a child had developed the potentially fatal form of cancer. The suspension was broadened to include an additional 27 trials yesterday "because of unanswered questions about what is going on," said Dr. Philip Noguchi, who is in charge of gene therapy issues at the FDA. But Noguchi cautioned that participants in the programs should not be unduly alarmed because an intensive study has revealed no cases of leukemia outside the French program.

Dr. Donald Kohn, who leads a trial halted at Children's Hospital Los Angeles, said the "clinical hold" was appropriate. "We need to find out why this has happened twice," he said.

An emergency meeting has been called for Friday by the Office of Biotechnology Activities at the National Institutes of Health to discuss the problem. The FDA has also scheduled a meeting Feb. 28 at which some of the trials could be reinstated. The suspension of trials represents another black mark for a field in which researchers have been widely criticized for promising more than they have been able to deliver and for rushing into clinical trials before most potential problems have been worked out. The biggest was the 1999 death of Jesse Gelsinger, 18, who suffered a violent reaction to a gene therapy treatment. "I have no doubt that the death of Jesse Gelsinger is going to lead to nothing but a cautious, go-slow approach," said ethicist Arthur Caplan of the University of Pennsylvania. "As a society, we're more nervous about genetics" than about any other form of medical therapy, he said.

Kohn said that, despite the new setback, he remained hopeful for the field. "We have to remember that seven of the 10 kids [in the French trial] were cured of an otherwise fatal disease" without developing problems, he said. "There is tremendous promise in gene therapy, but this specific approach may be a problem and we may need to look for other ways to use gene therapy in this disease."

Gene therapy seeks to replace defective genes with healthy genes to reverse genetic disorders. Researchers believe it is the only potential treatment for many inherited diseases. The two children who developed leukemia were among 11 infants with a disease, known as X-linked severe combined immune deficiency (X-SCID), treated with gene therapy by Dr. Alain Fischer and his colleagues at the Necker Hospital for Children in Paris. The illness is commonly known as "bubble boy" disease. The children have a defective gene, called GammaC, which prevents them from developing immunity against infectious diseases. Untreated, such children die within the first year of their lives from severe and recurrent infections. Some victims are successfully treated with a bone marrow transplant from a sibling who is a perfect match, but such matches are not often available.

Fischer used a so-called retrovirus to insert a healthy copy of the gene into the children's hematopoietic (blood-forming) cells. His trial was widely hailed because nine of the 11 children apparently were cured of their disease and were able to go home. But in October, one of the children, now 3, was found to have leukemia. Leukemia has a 90 percent cure rate with chemotherapy, and the child is reportedly doing well under treatment.

But U.S. officials concluded that the leukemia was a direct result of the gene therapy, and they halted three U.S. trials that had very similar protocols. Those included two trials at Children's Hospital. Kohn said researchers there voluntarily suspended a third trial - involving treatment for pediatric AIDS - that had not yet begun. Now that a second leukemia case has been discovered, FDA halted all trials in which retroviruses are being used to insert genes into hematopoietic cells. The American Society of Gene Therapy said yesterday that it will organize an ad hoc committee to review such trials to learn whether the leukemia is unique to the French trial or a more common problem.

Thomas H. Maugh II is a reporter for the Los Angeles Times, a Tribune Publishing newspaper.

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BBC News Wednesday, 15 January, 2003, 10:56 GMT

Cancer case raises gene therapy fears
A second case of leukaemia among children given
a revolutionary form of gene therapy has
increased concerns about the treatment.

picture: Rhys Evans was 'cured' of X-SCID by gene therapy

The patient, from France, was a boy "cured" of a condition called X-SCID, popularly known as "bubble boy disease". This genetic defect leaves children without an immune system - they need to be kept in sterile conditions or might catch fatal infections. The treatment involves taking the faulty immune cells from the child's bone marrow, genetically modifying them in the laboratory so they work properly, then putting them back to kick-start the immune system.

Four children have received similar pioneering treatment in the UK at Great Ormond Street Hospital in London. It appeared to work perfectly in many of the patients given the treatment. However, another French boy who was treated at the Necker Hospital in Paris fell ill with a leukaemic illness late last year. Both boys are said to be responding to treatment and are "stable", but the emergence of another case is a severe blow to the development of gene therapy.

Trials stopped

The Food and Drugs Administration in the US and the French authorities have now suspended the treatment, and many other trials involving a similar gene modification technique. In the UK, no further X-SCID gene therapy will be carried out until the question marks over safety have been resolved. Stephen Cox, from Great Ormond Street Hospital, told BBC News Online that all the four UK patients were well. He said that the hospital was liaising closely with the body that regulates gene therapy in the UK. He said: "Every family on the trials was briefed on the possibility that gene therapy might cause cancer but two patients out of the dozen or so on the French trial is clearly a matter for concern. "It would be highly premature to reach any final conclusion until we have the full facts. We do not know if the risks on the French programme are the same as ours."

Dr Harry Malech, of the National Institute of Allergies and Infectious Diseases in the US, told Reuters: "I think we shouldn't view this as the death knell to gene therapy. "We need more good science to work out what went wrong."

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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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January 23, 2004

Tracing the Cause of Leukemia in Gene Therapy Trial

Last year, researchers in France halted a gene therapy trial because two young patients developed leukemia. The patients suffered from a rare genetic disorder caused by a missing immune system gene. In October, researchers determined that the delivery of the missing gene was somehow activating a known cancer-causing gene in the patients' genomes.

Now a new study in mice offers an explanation of what went wrong. Researchers from the National Cancer Institute in Frederick, Maryland, report in Science that the gene delivered to the patients is itself a possible cancer-causing gene.

The high incidence of leukemia perplexed researchers. Ninety-nine percent of the genome doesn't code for any genes at all. The likelihood of the missing gene getting inserted within or near any gene, much less a cancer-causing gene, was thought to be extremely rare. But out of 10 patients enrolled in the trial, two had the same insertion in the same gene and both developed leukemia.

The patients were being treated for severe combined immune deficiency, also known as the bubble baby disease because patients have such compromised immune systems that they must live in isolated environments. The patients were missing a gene called IL2RG.

Replacing the gene effectively cured the immune disease, but caused leukemia in the two patients. These patients have been treated with chemotherapy and are in now in remission. No other patients have developed leukemia.

Most studies show that in order for any cancer to develop, several cancer-causing genes must be disrupted within the same cell. Inserting one cancer-causing gene into another cancer-causing gene increases the chances that leukemia could develop, according to Neal Copeland who led the recent study.

"Cancer doesn't result from one mutation," says Copeland. "But our data suggest that putting a cancer gene in a virus causes it to be overactive. By itself, it's not enough to cause cancer. But if it happens to land near another cancer-causing gene then you get cancer."

Copeland has developed a database that contains a long list of potential cancer-causing genes in mice. He has found two tumors in mice with insertions in IL2RG, the gene replaced in the gene therapy trial. He also found two tumors with insertions in the same gene that became activated in the leukemia patients. And he found one tumor with insertions in both genes.

In the trial, the replacement gene was overactive and not regulated the same way it is in a normal cell. As a result, says Copeland, cells expressing the replacement gene could grow better than those without the gene.

In a few rare cells, the replacement gene ended up near another cancer-causing gene, and cells could grow even faster. It's likely that these fast-growing cells rapidly replaced healthy cells in the patients' blood, causing leukemia.

"Before conducting any further gene therapy trials it might be wise to first check our database and see if the gene of interest is a potential cancer-causing gene," says Copeland. "If the gene is listed in our database, it might not be a wise choice for gene therapy."


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