ASGT Press Release 

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

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

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

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

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

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

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

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

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

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

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