A history of gene therapy

Abstract

The short history of human gene therapy is characterized by a mix of both quantum and incremental advances, as is true of most conceptually new areas of biomedicine. It is also marked by several unusual—and perhaps even unique—features. Gene therapy is a principal driving force in modern medical thinking even before it has proven itself rigorously in the clinic. In addition, based entirely on high expectations and the obvious correctness of its concept, initial academic efforts in gene therapy have spawned a huge parallel biotechnology and pharmaceutical counterpart. This combination not only has provided an enormous catalytic effect on the scientific and clinical translational enterprises underlying gene therapy, but has exacerbated the challenges posed by any major new technology to the academic–industrial–governmental partnership that conducts and supports it. It is very clear now that the concepts and the admittedly blunt tools of today's approach to gene therapy are taking the field of human gene therapy past the stage of theory to demonstrable clinical benefits in real patients with real disease. During the past year, very encouraging results of documented and quantifiable therapeutic benefit have been reported in several human studies, including what seem to be real phenotypic corrections of an X-linked form of severe combined immunodeficiency disease and of factor-IX-deficiency hemophilia B. These studies are not the result of quantum “breakthroughs” but rather of slow, steady incremental improvements in all aspects of study. But it has been a bumpy road. In its short history the field of gene therapy has been beset with several major clinical and public policy setbacks that have cast deep doubts on the quality of the scientific effort and its clinical translation. Several of the most highly visible early studies were described and carried out in overly expectant and optimistic terms, promising far more than they could deliver and thereby carrying with them the seeds of their own failure. The miscalculation can be seen among exaggeratedly optimistic investigators, research institutions, interest groups, and scientific and lay press. The effect of these missteps has been to incur the public displeasure of the director of the National Institutes of Health and, after the first documented gene-transfer-related death of a patient, major changes in the procedures for public review and regulation of clinical translation of gene therapy. This combination of advances met step-for-step by serious setbacks has had the additional unfortunate effect of blunting some of the wonder that should have accompanied the recent positive clinical studies. It has also caused at least transient damage to the public and public policy credibility of the field. The purpose of this series of articles on the history of gene therapy is to chronicle some of the most important technical and clinical events, advances as well as setbacks, that have shaped current human gene therapy. As is always the case, many contributions from many investigators have led most of us to a state of great confidence that gene transfer and gene correction technology will continue to evolve; that vectors will finally be able to deliver therapeutic genetic information efficiently and specifically to appropriate target cells; and that clinical application will be increasingly successful as our understanding of disease pathophysiology, pathogenetics, and gene regulation and manipulation expands. With the very encouraging recent clinical results and the first draft of the entire human genome sequence (and thus the anticipated and inevitable flood of genetic disease targets), more pressure to move from an understanding of the human genome to its therapeutic manipulation will undoubtedly result. An appreciation of the history of the field, as reflected in this series, will make it all the more stunning how important this pioneering work has been.