Plus ça change…
Authors: Theodore Friedmann
Journal: Molecular Therapy (2003)

In 1995, NIH Director Harold Varmus appointed two ad hoc advisory committees, one chaired by Arno Motulsky and Stuart Orkin and the other by Inder Verma, to examine the impact of early clinical gene transfer studies on the scientific and public credibility of the field of human gene therapy. The committees concluded that results from some stud- ies were hyped and that exaggerated claims raised unrealistic hopes. Coming on the heels of disappointing results in clinical studies of gene transfer to treat cystic fibrosis, ADA-SCID, familial hypercholesterolemia and others, the NIH report catalyzed a restructuring of the role of the NIH Recombinant DNA Advisory Committee (RAC) in the review of clinical gene transfer studies and inspired a more sober public posture for the field. Since that time, there has been comfortingly less hype and increased circumspection in the preparation of clini- cal trials and in the the presentation of clinical results to both scientific and lay audiences. Recently, reports have appeared describing the initiation of a clinical gene transfer study in subjects with Parkinson's disease. The study is based on an unconventional concept of treatment of this disease that aims to alter neuronal function within the affected region of the brain rather than simply to enhance levels of dopamine production. This new approach is supported by some preclinical studies conducted in rodents and certainly deserves rigor- ous basic and clinical follow-up studies. Based on these studies and on some preliminary primate experiments, the investigators proposed a clinical study that has been reviewed over the past two years by the appropriate local institutional committees, as well as by the FDA and the NIH RAC. The announcement of the enrollment and vector implantation in the first subject of the study was covered extensively by the mass media. The story appeared on the front page, above the fold, in the New York Times (August 19, 2003), on network news programs, and even included apparently invited photo coverage from the operating room during the surgical procedure. While most reports noted the preliminary nature of the study, the tone of many of them was nevertheless bullishly enthusiastic about an impending treatment for Parkinson's disease, which seems overly optimistic given that the subject was only the first to receive the vector in a phase I safety study. Following the announcement, many comments from basic scientists, clinicians and foundations working on this disorder were more reserved. Some were even critical of both the scientific under- pinnings of the study and of the way in which it seemed to have been manipulated for maximal public effect before its safety and relevance to the neurophysiological defect was fully demonstrated in the most appropriate animal model—a monkey showing signs and symptoms similar to those of the human disease. The path that this study took to the clinic contrasts strongly with that of the recent X- SCID studies (see Vol. 8, pp. 5_7). Sadly, it appears that the lessons and sober warnings of the Motulsky-Orkin report have not had their full impact in the gene therapy community. In the case of the X-SCID studies, hopes for therapeutic efficacy and relief from the grips of a terrible disease were understated until issues of safety were studied in the available ani- mal model closest to the human disease and until apparently beneficial clinical effects were demonstrated, even in the context of terrible adverse consequence of leukemia develop- ment in two children resulting from the gene transfer. In the Parkinson's study, the flames of hope and expectation in desperate patients seem to have been stoked to levels that, given the difficulty of this disease model, are at risk of leading to crushing disappointment or serious adverse consequences. The appropriateness of early studies in human clinical research should be judged a priori by their design and not primarily by their eventual results in patients. Failure to take to heart the important advice of the Motulsky-Orkin report risks once again dashing the hopes of patients and of damaging the credibility and public sup- port of this important new field of medicine. The views expressed in this editorial do not necessarily represent the views of the RAC or of the NIH.