A New Serious Adverse Event in a Gene Therapy Study
Authors: Theodore Friedmann
Journal: Molecular Therapy (2007)

Attention was recently focused on the tragic death of a patient in a gene therapy study of severe rheumatoid arthritis. The patient was a relatively young woman suffering from long-standing but not life-threatening disease. The facts underlying her death are not yet clear. But there is no convincing evidence that this patient's death was caused by the intra-articular injection of the AAV vector, as was prematurely and so forcefully implied in some initial press reports. Of course, the study was placed on clinical hold until the causes of death could be ascertained, and questions as to whether and how to proceed with this study must obviously await the outcome of many ongoing investigations. Nevertheless, several things are already clear about the occurrence of such serious adverse events and their implication for the field of gene therapy. Rigor and prudence require that we always examine all serious adverse events to rule out a connection with the experimental procedure when no connection exists. Equally important, we must always be prepared to identify those rarer instances in which adverse events are truly related to the experimental procedure and that, therefore, require a change of experimental design. Gene therapy is still a highly experimental and immature field of biomedicine that, after approximately 17 years of clinical applications, has finally begun to demonstrate incontrovertible clinical therapeutic efficacy in several serious diseases, including cancer and childhood immunodeficiency. No knowledgeable observer can any longer deny that, in this small but growing set of human diseases, the gene transfer approach has become “therapy”—imperfect, but nonetheless therapy. Sadly, however, as with most other areas of experimental medicine, the enormous gaps remaining in our understanding of disease mechanisms and gene transfer technologies still prevent trouble-free application of current gene therapy concepts and tools in human clinical studies. They even guarantee continuing occasional setbacks and serious reversals; that's the nature of clinical research. Unfortunately, particularly to some media observers, that fact brings into question the very rationale for clinical research in gene therapy. One even asked me whether this setback “pulls the rug out from under gene therapy.” Medicine does not have the luxury of standing still awaiting perfect understanding. In our culture, treatment of disease is a moral imperative that at times requires application of even imperfect methods. We understand that things will inevitably go wrong, even in some of the best-designed and most carefully carried out studies; patients will be harmed, and some will die from unexpected and unpredictable setbacks. Why does this continue to surprise some? Modern medicine relies on many forms of therapy that, early in their development, went through long periods of disappointment, setbacks, failures, and patient injuries and even deaths before the underlying conceptual and technical unknowns were finally understood well enough for them to become indispensable parts of medical therapy. Medicine without these now central technologies—bone marrow transplantation, cancer chemotherapy, monoclonal antibodies for targeted drug delivery—would be impoverished. Bone marrow transplantation—so lifesaving today—began in 1958, and, by the early 1970s, the survival from the procedure was around 1%. Chemotherapy for childhood leukemia began in 1948, and, well into the 1960s, the cure rate was below 10%. In both cases, about three decades of continuing research were required before the reasons for early failures were understood well enough to enable the development of what we would willingly call “therapy.” Three decades seems to be a good rule-of-thumb time for many new technologies to find their way to effective therapy. Even now there are many failures and setbacks; we are still not perfect. Now, after only approximately 17 years of clinical gene therapy experience, we have started to see incontrovertible and growing evidence of therapeutic benefit for some patients with immune defects, forms of cancer, and other serious illnesses. At the same time, there have been several very important serious setbacks and adverse events that impress on us how immature the technology is. In truth, there have previously been very few such serious setbacks—two documented deaths of patients as a direct result of their gene transfer procedures and a handful of other serious, even life-threatening responses. Now we face this patient death in the arthritis study. Yet with each new major setback seems to come the inevitable history-blind questions of whether such occurrences indicate failure of the concept of gene therapy itself. The answer is that they do not denigrate the concept of gene therapy; they merely remind us how far we still have to go. With history in mind, gene therapy should not be held to an unachievably high standard not demanded of many other areas of new therapies—a standard by which each failure or setback is seen to be a threat to the concept itself. Rather than discourage us, those events should simply catalyze us to make even more effective efforts to solve problems posed by present concepts and techniques. One issue that becomes particularly important following the recent death concerns patient selection and the design of clinical gene therapy studies for nonlethal disease. An effective discussion of this question should be one of the important positive outcomes of this tragic event.