Success and Setback: Another Adverse Event
Authors: Inder M. Verma
Journal: Molecular Therapy (2002)

On April 30, 2000, The New York Times published an editorial entitled, “Success in Gene Therapy, at Last,” referring to the first successful use of gene therapy to treat a human disease. Severe combined immunodeficiency disorder (SCID)-XI is caused by mutations in the X-linked gene IL2RG, which encodes the common γ–chain (γc) of the lymphocyte receptors for interleukin-2 and many other cytokines. SCID is commonly known as “bubble boy disease,” referring to a young boy, David, who, suffering from a similar condition, spent his entire life in an airtight “bubble” to avoid contact with microbes. Alain Fischer, Marina Cavazzana-Calvo, and colleagues at Hopital Neckar-Enfants Malades in Paris had harvested bone marrow from two infant boys suffering from SCID-XI, aged 11 months and 8 months, and had transduced the cells with a Moloney murine leukemia viral vector expressing a normal copy of the γc cDNA. The transduced cells were then infused into the infants. When untreated, these patients usually die within the first year of life, whereas nine infants in France treated in this manner are now living completely normal lives. Now comes the news that a routine checkup on the third infant treated with the gene therapy at one month of age revealed an excess of T lymphocytes in the blood. A press release dated October 3, 2002, from the French Medicine Agency (AFSSAPS) explained that the T-lymphocyte counts of this child (now three years old) rose to an abnormally high number at the end of August, and that the child has shown clinical manifestations associated with T-cell leukemia. Further investigation has revealed that the aberrantly proliferating lymphocytes are monoclonal, are of the γ/δ receptor-expressing subtype, and that the vector had inserted itself in the chromosome near a gene, LM02, known to be involved in angiogenesis, a hallmark of cancer cells. Although this gene is normally not expressed in this subset of T lymphocytes, expression can be detected in the aberrantly proliferating cells in this patient. The implication is that viral vector insertion led to the expression of LM02, a phenomenon known to retrovirologists as insertional mutagenesis. No replication-competent retroviruses (RCR) have been identified in this patient or in any of the more than 100 patients treated with a wide variety of retroviral vectors. It has long been known that retroviral vectors insert randomly into the chromosome–and therefore carry the risk of activating a dormant gene or deactivating an active one–but very extensive preclinical studies and the lack of any adverse events in over 100 patients treated with related vectors suggest that the phenomenon of insertional mutagenesis is extremely rare. Nevertheless, the risk of cancer as an adverse side effect of gene therapy by retroviral vectors is stated explicitly in the informed consent statement that describes the risks and potential benefits to the patients and their families. In the unfortunate case of the child in the French trial, numerous additional investigations are needed to decipher the precise mechanism responsible for cell proliferation, which should include the nature of the origin of the LM02 transcript, the family predisposition to cancer, and the presence of any chromosomal rearrangements. After confirming the aberrant proliferation of T lymphocytes in the treated patient, Dr. Fischer promptly informed the appropriate regulatory authorities in France, the United States, and investigators involved in similar clinical trials worldwide. This has led the FDA in the U.S. and AFSSAPS in France to halt similar clinical trials until more is known about the precise cause of the adverse event. In contrast, the gene therapy advisory council (GTAC) in the United Kingdom has decided to move ahead with two trials to be carried out at the Great Ormond Street Children's Hospital. Dr. Norma Letvin, chair of the GTAC, says, “It is a great ethical dilemma.” The treatment of choice is a bone marrow transplant from a normal brother or sister. Unfortunately the majority of patients with SCID lack such a perfect “tissue type match” and therefore gene therapy is an attractive treatment. It is worth noting that clinical trials using gene therapy to treat this disease have led to immune recovery in over 90% of treated infants–infants who would otherwise have had little or no chance of survival. Like all new experimental therapies, there are inherent risks to gene therapy. As with all clinical research, patient safety is of paramount importance and every effort should be made to minimize these risks. Researchers are busy designing the next generation of vectors and transduction protocols. The gene therapy community has become very vigilant and quickly shares information on any and all adverse events that may have an impact on related clinical trials. It is important that the process of reporting adverse events and subsequent actions by regulatory authorities remain totally transparent. We must not fail to communicate honestly to the public of the risks and the unexpected events with the same vigor with which we tout the benefits of gene therapy in curing diseases and improving the quality of human health.