Gene Therapy on the RAC
Authors: Fintan R. Steele
Journal: Molecular Therapy (2000)

By all accounts, the December 8–10 meeting of the ad hoc working group of the NIH Recombinant DNA Advisory Committee (RAC), cochaired by Claudia Mickelson and Inder Verma, was a good one. The open sharing of unpublished data; the coming together of industry, government regulators, and academicians; honest discussions looking for common grounds: This is the way gene therapy should advance. But the circumstances that prompted this exceptional gathering—the death of a young volunteer in a gene therapy protocol at the University of Pennsylvania and the subsequent revelation of alleged reporting lapses in other gene therapy trials—taint this vision of the scientific peaceable kingdom. Nevertheless, whatever observers were expecting (and premeeting speculation ranged from a FDA vs NIH showdown on regulatory authority to a public lynching of the UPenn research group for perceived regulatory lapses), what ultimately transpired was fairly positive and constructive, despite its painful origins. Although gene therapy may be down, it is hardly out. The stated aims of the RAC committee meeting were twofold. The first was to evaluate the data from the unfortunate UPenn death in the context of all other known data about the use of adenovirus and, to some degree, other vectors and come up with a set of recommendations for future action. The second was to revisit the question of adverse effect reporting in the context of gene therapy trials. This commentary outlines the results of discussion of possible recommendations. It must be said that none of these are new concerns, although the UPenn incident has focused them and given their resolution a sense of urgency. The matter of adverse effect reporting is addressed in a statement given to the RAC by Savio L. C. Woo, ASGT president, which is published in this issue of Molecular Therapy (1Woo S.L.C. Policy statement of the American Society of Gene Therapy on reporting of patient adverse effects in gene therapy trials.Mol. Ther. 2000; 1: 7-8Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). It is difficult, perhaps impossible, to compare clinical and preclinical trials without some standard against which to compare dosage. Should comparison be based on particle number (the current standard, with no guarantee that different ways of measuring give directly comparable numbers), pfus, or some combination of the two? It is clear that similar numbers from two different trials using adenoviral vectors (or other vectors) do not translate to the same dose given in both trials. The ASGT has offered to work with the FDA to come up with a set of standards and protocols to overcome this significant problem. Another significant problem is the evaluation of efficacy of gene transfer. It is clear that there must be some standard method or methods for quantifying the expression of the gene introduced. Furthermore, it is also necessary to quantify the proportion of cells within a target tissue that can be transduced. Obviously, any method will be highly target-dependent as well as vector-dependent. Finally, more than anecdotal evidence is required to document any clinical effects that arise following gene transfer in order to evaluate efficacy. How does one select trial candidates and then follow them through the trial? It is clear that the immune status of a possible enrollee plays a vital role (i.e., their existing immune response to both the vector used and the transgene product). The presence of possible secondary infections, which may have played a role in the UPenn death, must also be evaluated. Finally, early and consistent profiling of relevant cytokines will have to become a regular part of patient monitoring both before and during the trial. Different routes and rates of administration as well as the vector used all have significant effects on the distribution of the transferred gene. The vast data already available should be mined for useful information, but this requires the construction of an organized and widely accessible database. The need for this fundamental tool, expressed many times before the most recent RAC meeting, underlines the paucity of resources committed to assembling such a directory. It is well established that vector titers can decline precipitously with even fairly minor handling. Thus, it is necessary to evaluate closely the quality and integrity of vector used in specific clinical trials and perhaps individual patients. This may mean analysis not only of each lot, but also of each prep. Of course, this depends on the establishment and implementation of as-yet-undefined standards. The question of including a control arm in gene transfer studies in humans (e.g., transfer of null vectors into some volunteers in any given trial) raises a host of thorny ethical questions. Nevertheless, such studies are absolutely required for bridging the gap between safety and efficacy. As one RAC member put it, “If a control is not done, we don't know how it works.” Mice are not humans, as we know. Neither are monkeys, really, at least in terms of some gene therapy issues (e.g., the difference in expression of the CAR receptor between monkeys and humans). Thus, it is critical to come up with better methods for evaluating preclinical results in relation to proposed human studies. This is another thorny issue, but one that may prove to be decisive in evaluating the risk of any given trial, particularly those under way using current adenoviral and other vectors. The UPenn researchers presented a wealth of postmortem data that will help focus attention on the factors that contributed to their patient's death. Nevertheless, in a context where autopsies are performed following only about 10% of all deaths, it may be difficult to obtain the necessary permissions to proceed. Thus, it may be useful to have an agreement for a postmortem examination written into the initial consent form. That said, it will still be difficult in some cases to sort out immediate effects of the gene therapy intervention from ongoing events related to disease. These eight points were the primary concerns identified and discussed openly during the meeting and from which recommendations will be issued. However, several panel members privately raised other concerns, including asking why adenoviral vectors should be used at all in light of current knowledge. Although a legitimate question under the circumstances, it is clear that these vectors will be useful in some manner in the growing armamentarium of the gene therapist, particularly in cases where the activation of the immune system is a desired goal. Prompt action on the issues raised above and any recommendations outlined by the RAC will help define that use. The other issue intensely discussed privately but seldom voiced publicly was the possibility of future sanctions against the UPenn group. I don't want to add to the speculation here, especially as the FDA is still in the midst of its investigation—a fact that makes the FDA's strong public statements to the press during the 3-day meeting a bit curious at best. Nevertheless, it is clear that there are adherence problems disciplinewide even to the current NIH and FDA rules. These “lapses” were also addressed to a degree at the RAC meeting, although not forcefully. It seems to me that a sound remedy, or at least a good starting point, is proposed in the statement given by ASGT President Savio Woo (1Woo S.L.C. Policy statement of the American Society of Gene Therapy on reporting of patient adverse effects in gene therapy trials.Mol. Ther. 2000; 1: 7-8Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). It is very clear that any reporting structure will depend in large part on privacy concerns. Perhaps an even more sensitive consideration is the increasingly uneasy relationship of academic centers and the biotech industry, an issue considered by Ted Friedmann in this issue of Molecular Therapy (2Friedmann T. Changing roles for academia and industry in genetics and gene therapy.Mol. Ther. 2000; 1: 9-11Abstract Full Text Full Text PDF Scopus (7) Google Scholar).