A Voluntary Moratorium?
Authors: Inder M. Verma
Journal: Molecular Therapy (2003)

Gene therapy is an experimental form of medical treatment, and experimentation in patients is necessary to evaluate its success. Although one can predict possible risks based on preclinical studies, the defining test is the treatment of real patients. How many experimental treatments fail in phase III clinical trials despite excellent preclinical data? It is often said that “the best model for the human is human,” and there is just no getting away from this dictum.Gene delivery vehicles that allow sustained production of a therapeutic gene due to its introduction into the host chromosome, while highly desirable, have a serious drawback. The site at which a vector or a therapeutic gene inserts into the genome is laregly unpre-dictable. Retroviruses can cause cancer by random insertion into the host genome, a phe-nomenon known as “insertional mutagenesis.” However, once the retroviral vectors were made replication-deficient, essentially no cancer was reported in hundreds of experimental animals and in dozens of clinical trials involving hundreds of patients. Because of this, regulatory authorities felt it safe to proceed with clinical trials in humans using retrovirus-mediated gene therapy.However, in September 2002, French researchers reported that a boy suffering from X-linked, severe combined immunodeficiency disease (SCID-XI), who had been treated with a retroviral vector expressing the common gamma chain (yc), developed an abnormal T-lymphocyte count—a hallmark of leukemia. Insertional mutagenesis was later established as the likely cause—the first established link between retroviral vector insertion and the development of neoplasia in a human patient. Subsequently, both the French group and the FDA in the United States halted similar clinical trials. Now comes news of a second adverse event, similar to the one reported in September 2002. While the precise details are still fragmentary, insertional mutagenesis is again the likely suspect. Two out of eleven treated children are now affected, and additional adverse events cannot be discounted.The regulatory authorities have obligations to patients that are defined by their charters. Yet how shall we, the practitioners of gene therapy, respond to this new situation? One pos-sible reaction is to propose a voluntary moratorium on retrovirus-mediated gene transfer into hematopoietic stem cells until more is known. While such a moratorium may appear prudent, what if it is the yc transgene and not the vector sequences themselves that impart the altered growth characteristics to the affected T cells? Such a problem may not occur with treatments for genetic diseases such as adenosine deaminase (ADA) deficiency, chronic granulomatosis disease (CGD), lysosomal storage diseases, and hematopoietic cancers, rendering a blanket moratorium for stem cell transduction both unwise and unfair to patients suffering from these potentially fatal diseases. Furthermore, perhaps the type of the retroviral vector used in the French trial was not ideal?No similar adverse events have been reported in hundreds of retrovirus-mediated gene marking or clinical disease trials, some carried out as long as a decade ago. Add to this the fact that children with SCID-XI are uniquely immunocompromised. The reality is that there are so many unknowns that a moratorium, even a voluntary one, may actually be inappropriate to the needs of patients suffering from incurable disease. Nevertheless, we face the dilemma that nearly 20% of the treated SCID-XI children have shown clear signs of abnormal T-cell proliferation. While we have a responsibility for patients’ safety, we have an obligation to science and to society to continue to find ways to combat incurable disease. Experimental medicine is fraught with risks, but the prospect of curing an incurable disease can be very rewarding. Molecular Therapy urges its readers to send us their opinions on this important discussion. Gene therapy is an experimental form of medical treatment, and experimentation in patients is necessary to evaluate its success. Although one can predict possible risks based on preclinical studies, the defining test is the treatment of real patients. How many experimental treatments fail in phase III clinical trials despite excellent preclinical data? It is often said that “the best model for the human is human,” and there is just no getting away from this dictum. Gene delivery vehicles that allow sustained production of a therapeutic gene due to its introduction into the host chromosome, while highly desirable, have a serious drawback. The site at which a vector or a therapeutic gene inserts into the genome is laregly unpre-dictable. Retroviruses can cause cancer by random insertion into the host genome, a phe-nomenon known as “insertional mutagenesis.” However, once the retroviral vectors were made replication-deficient, essentially no cancer was reported in hundreds of experimental animals and in dozens of clinical trials involving hundreds of patients. Because of this, regulatory authorities felt it safe to proceed with clinical trials in humans using retrovirus-mediated gene therapy. However, in September 2002, French researchers reported that a boy suffering from X-linked, severe combined immunodeficiency disease (SCID-XI), who had been treated with a retroviral vector expressing the common gamma chain (yc), developed an abnormal T-lymphocyte count—a hallmark of leukemia. Insertional mutagenesis was later established as the likely cause—the first established link between retroviral vector insertion and the development of neoplasia in a human patient. Subsequently, both the French group and the FDA in the United States halted similar clinical trials. Now comes news of a second adverse event, similar to the one reported in September 2002. While the precise details are still fragmentary, insertional mutagenesis is again the likely suspect. Two out of eleven treated children are now affected, and additional adverse events cannot be discounted. The regulatory authorities have obligations to patients that are defined by their charters. Yet how shall we, the practitioners of gene therapy, respond to this new situation? One pos-sible reaction is to propose a voluntary moratorium on retrovirus-mediated gene transfer into hematopoietic stem cells until more is known. While such a moratorium may appear prudent, what if it is the yc transgene and not the vector sequences themselves that impart the altered growth characteristics to the affected T cells? Such a problem may not occur with treatments for genetic diseases such as adenosine deaminase (ADA) deficiency, chronic granulomatosis disease (CGD), lysosomal storage diseases, and hematopoietic cancers, rendering a blanket moratorium for stem cell transduction both unwise and unfair to patients suffering from these potentially fatal diseases. Furthermore, perhaps the type of the retroviral vector used in the French trial was not ideal? No similar adverse events have been reported in hundreds of retrovirus-mediated gene marking or clinical disease trials, some carried out as long as a decade ago. Add to this the fact that children with SCID-XI are uniquely immunocompromised. The reality is that there are so many unknowns that a moratorium, even a voluntary one, may actually be inappropriate to the needs of patients suffering from incurable disease. Nevertheless, we face the dilemma that nearly 20% of the treated SCID-XI children have shown clear signs of abnormal T-cell proliferation. While we have a responsibility for patients’ safety, we have an obligation to science and to society to continue to find ways to combat incurable disease. Experimental medicine is fraught with risks, but the prospect of curing an incurable disease can be very rewarding. Molecular Therapy urges its readers to send us their opinions on this important discussion.