Stakeholders’ Conference Sharpens Focus on Challenges of Clinical Gene Transfer
Authors: Katherine A. High, David A. Williams
Journal: Molecular Therapy (2005)

This year's annual meeting of the American Society of Gene Therapy (ASGT) provided ample evidence that the science of gene transfer is moving forward at an exciting pace. Indeed, it has been gratifying to see the focus of scientific sessions shift from a preoccupation with methods for better gene transfer to what might be called “second-order problems” of gene transfer, such as the immune responses to the vector and its transgene product, and the risk of germline transmission, for example. However, there is also a general sentiment that clinical work in gene transfer is proceeding slowly despite rapid advances in the science. In April of this year, the ASGT sponsored a conference held in Washington DC that was designed to identify factors that are slowing progress in clinical gene transfer. Dubbed the “Stakeholders’ Conference,” the premise was to ask leaders in the field to review their own experiences in carrying out clinical studies and to share obstacles they had encountered with other attendees. In an opening address at the conference, I listed a number of factors that are frequently mentioned as obstacles to progress in clinical gene transfer. Although these run the gamut from fragmented intellectual property to availability of clinical grade vector, three obstacles emerged as recurring themes in speakers’ presentations. The first of these is the complexity of the regulatory processes to which gene therapy trials are subjected. Malcolm Brenner presented the liveliest pictorial representation of this process, depicting the regulatory agencies as a multi-headed Hydra with the investigator caught in its grasp. Indeed, nearly all investigators noted that the multiple layers of regulatory oversight contributed to delays in their timelines. Currently, an NIH-sponsored academic protocol needs to be reviewed and approved by the NIH RAC, a separate and distinct NIH Data Safety and Monitoring Board, a local institutional review board, an institutional biosafety committee, and the FDA Office of Cell, Tissue and Gene Therapy. Although the purpose of these reviews is, amongst other considerations, to ensure the safety of subjects who enroll in the trials, one can legitimately ask whether additional layers of review contribute to greater safety. A number of investigators cited the value of input from the FDA, whose professional reviewers have a unique perspective arising from access to a wide range of data that may not be available elsewhere. The development of new classes of therapeutics is critically dependent on the availability of scientist regulators who can help to set a reasonable course for drug development and eventual licensure. However, retention of first-rate reviewers is threatened by a lack of resources at the FDA, whose budget growth has not kept pace with that of many other governmental scientific agencies in the past decade. In light of this, it seems shortsighted to persist with a system that fragments regulatory resources amongst multiple groups. A more efficient and cost-effective approach might be to concentrate resources in the hands of, for example, one federal and one local review body, as is the case for other classes of therapeutics. An important goal for the ASGT as the field moves forward is to promote the idea of a less complex and labyrinthine regulatory process. The complexity of the regulatory process—and the ensuing delays as this complex system is navigated—have exacerbated the second obstacle, which is the identification of funding for clinical investigation in gene therapy. There has been a gradual reduction in participation from the biotech sector as the timelines become too long for their investors. This is particularly unfortunate because the biotech sector has repeatedly been the engine of progress in the development of novel therapeutics. Investigators tend to use disease foundation and/or NIH support to fund preclinical and even early-phase clinical testing, and then partner with biotechnology and pharmaceutical companies to conduct laterphase clinical studies and licensing. However, there are broad middle stages of the work that NIH funding mechanisms have not traditionally been structured to support. The NIH has recognized this problem and has begun to respond in terms of new RFAs directed at clinical and translational work in gene therapy. It will be critical for them to continue valuable programs that have provided clinical grade vectors, and expand these to include vectors currently in heavy demand, such as AAV and lentiviral vectors. Disease foundations have also begun to earmark funds to support gene therapy trials. It is likely that as clinical work proceeds, many safety issues that now slow clinical development will be addressed, allowing clinical studies to proceed at a pace similar to that of other therapeutics, and thus facilitating more robust participation by biotech and pharmaceutical companies. The third obstacle is the poor public perception of gene therapy, which has had an impact on many areas of this field's development. Overly optimistic expectations for early success were followed by high profile press coverage of adverse events. The result has been widespread public perception that gene therapy is failing to meet its promise and that it is generally unsuccessful or even dangerous compared to other investigational drugs. The ramifications of this are extensive. Potential trial subjects are reluctant to participate in clinical studies, new start-up companies have trouble finding financing, more established companies reduce their efforts in the area, and funding agencies, public and private, question the wisdom of further investment in the field. It is probably prudent to recall that similar cycles of enthusiasm and skepticism accompanied the development of monoclonal antibodies as a therapeutic agent, with initial ebullience giving way to negativism when the first clinical trials failed to meet with success. As most scientists know, however, the early clinical studies helped to identify problems that were eventually solved, allowing monoclonal antibodies to become the clinical and commercial success that they are today. That process took time, and the successful development of gene therapy will likely take time as well. The ASGT must work to ensure that public perception of gene therapy is closer to reality. Although there are problems that will need to be solved to achieve widespread applicability of gene therapy, the number of successes grows each year, and the list of scientific problems blocking clinical development continues to shorten. In this issue of Molecular Therapy, Themis et al. report the development of hepatic tumors in mice injected during fetal or neonatal periods with a nonprimate lentiviral vector. The intriguing data suggest that both fetal and neonatal mice are highly sensitive to side effects of vector integration. The authors appropriately comment on the lack of causal mechanism in this study, although they provide evidence that the inclusion of the WPRE sequence of the Woodchuck Hepatitis Virus in similar lentiviral backbones in this same model does not appear to increase the frequency of tumor formation over background. This is of some importance, as expression of the truncated WHx gene has been previously suggested to be potentially oncogenic in hepatic tissue and many state-of-the-art lentiviral and retroviral vectors contain this genetic element to enhance expression and/or titer. While these data are clearly provocative, the lack of understanding at the molecular level, the unknown impact of vector dose, the clear differences reported in the behavior of EIAV-based compared to HIV-based vectors, and the rather unique model employed in the study all require some caution in extrapolation of these results to the broader application of lentiviral vectors. As we have observed repeatedly over the past twenty years, these results will very likely lead to increased research focus at the basic level and increased understanding of viral vectors and oncogenesis.