Gene therapy in the United States: A five-year status report

Clearly, gene transfer therapy has caught the interest, imagination, and hope of the public, industry, and academia. The most remarkable and compelling aspect of the clinical applications of this technology so far has been the lack of significant toxicity directly related to gene transfer in the numerous Phase I trials. It is important to recognize that problems, such as the production of replication-competent retroviruses and the possibility that adenovirus-containing recombinant agents will shed and spread remain of concern. However, the current regulatory approach has been adequate to prevent significant new problems in these early trials. Gene marking protocols have advanced the science of autologous transplantation and may be expected to be part of experimental evaluation of new approaches to transplantation for the next several years. The most important finding of the marking trials for the future of gene therapy is that genes may be expressed in vivo in hematopoietic progenitors-immature stem cells that are the source of succeeding generations of circulating blood cells. Effective transduction of stem cells would enable the maintenance of genetic reagents in the human body for several years or even, possibly, for the life-time of the individual. It is clearly too early, however, to assess the therapeutic efficacy of gene therapy or even to predict its promise. Numerous studies have reported the ability to express recombinant DNA in vivo, but few have reported clinical efficacy. Gene therapy is still at an early stage and nearly all of the studies consist of Phase I trials, with the goal of establishing safety, rather than efficacy, of the procedure. It is difficult to discern whether the small number of cases of clinical improvement are directly attributable to gene therapy or merely to spontaneous remission of disease or to other forms of medical intervention provided simultaneously with gene transfer. The few 'dramatic' successes claimed are not dissimilar to those that were reported with a variety of other therapeutic techniques for which enthusiasm ultimately dampened over time. This is not to say that gene transfer therapy is a failure or that it should be abandoned. Rather, the data presented in this report emphasize that even after 5 years of clinical work, there remains a need for a further effort directed at improving the basic technology. Recognizing the problems so far in demonstrating clinical efficacy and the necessity of establishing a clear focus for the field, the Director of the NIH established a panel of experts to provide recommendations regarding future NIH-sponsored research in human gene transfer. In addition to stressing the need for greater scientific rigor, with the development of well-defined experimental hypotheses and quantifiable molecular and clinical end points as the underpinning of future studies, the panel has emphasized the need for effort in three areas. The first is the development of vector technology and an understanding of the biological interaction of vectors with the host. Vectors need to be developed to increase and maintain an adequate level of gene expression in somatic cells over prolonged periods to achieve cell-specific or tissue-specific expression and to regulate gene expression within the cell. The second area to be developed is a basic understanding of disease pathogenesis. Defining the mechanisms by which gene mutations lead to disease would be a crucial step toward conceptualizing new treatment strategies. Furthermore, knowledge of disease pathophysiology should lead to better understanding of which cell types in the body are appropriate targets for effective therapy, what levels of gene expression are required for clinical effectiveness, and how to regulate gene expression once genes have reached the target cells. The third area recommended by the panel is the future development of animal models, both of naturally occurring and genetically altered animals, to test experimental hypotheses and specific therapies prior to trials with humans. The panel likened the progress of gene therapy to that of bone marrow and organ transplants, which required several decades of trial and error before reaching its current status of acceptability for patients with life-threatening disease. In sum, while the public has anticipated that this new form of therapy will lead to novel medical cures, it is still too soon to tell if and when gene therapy will achieve its goals.