The 3rd Cabo Gene Therapy Focus Panel: On the Offensive for Biodefense
Authors: Robert M. Frederickson
Journal: Molecular Therapy (2003)

September 11, 2001 marked a significant turning point in both American and world history. The specter of terror- ism is now a reality that we all must live with every day. Our vulnerability to bioterrorism in particular was laid bare by the anthrax mailings that followed soon after the physical attacks on New York City and Washington D.C. Biological terrorism and the response to this growing threat by both governments and society as a whole pose new opportuni- ties—as well as new challenges—to the medical research community. The U.S. federal government has been quick to respond to the bioterror threat by earmarking new funds to combat it—nearly $6 billion dollars in 2003 alone. In February 2003, the current U.S. administration announced “Project Bioshield,” which it defined as “a comprehensive effort to develop and make available modern, effective drugs and vac- cines to protect against attack by biological and chemical weapons or other dangerous pathogens.” An important component of this initiative is to strengthen the ability of the National Institutes of Health to research and develop new bioterror countermeasures. Furthermore, the project mandates giving the Food and Drug Administration (FDA) the capacity to speed the availability of new treatments in the wake of a crisis. The gene therapy and vaccine development communities are key targets for this initiative and the response to bioter- ror in general. Gene therapy research has focused on the development of viral and nonviral vectors to transfer thera- peutic and protective genes to target cells to prevent and treat disease—and these efforts are clearly applicable to biodefense efforts. Moreover, gene therapy researchers pos- sess the expertise to take viruses apart and to engineer new vectors from them. U.S. military researchers have been developing countermeasures for state-sponsored biological weaponry for much of the last century—research and know- how that is directly applicable to the growing bioterror threat. Many actual and potential biological weapons, such as Ebola, anthrax, and smallpox, have been under study for some time prior to 9/11. The objective of the 3rd Cabo Gene Therapy Focus Panel was to gather together a diverse panel of researchers from the gene therapy, vaccine, and military biodefense communities to discuss the new challenges of defense against bioterror, to examine the potential contribu- tions that the gene therapy community can bring to this effort, and to identify ways that the new biodefense initia- tives might impact the field of gene therapy. A key outcome of the meeting was the realization that there is vast untapped potential for synergy between the government and military personnel responsible for bioterror countermeasures and the researchers in the gene therapy community. “Effective communication and collaboration between the Department of Defense laboratories and the academic and biotechnology sectors is going to be critical in biodefense, and this meeting marked an initial dialogue,” says Darrell Galloway, Deputy Director Biological Defense Research Directorate, Naval Medical Research Center (Silver Spring, MD). “Traditionally, gene therapists and bioterrorism experts live in different worlds,” adds Ronald Crystal, pro- fessor of medicine at Cornell Medical College, “At the Cabo meeting, it became obvious to all of the participants that gene transfer technology is very applicable to developing strategies to prevent and treat disease associated with a bioterror attack.” Gene therapists and virologists possess a great deal of experience with genetic modification of viruses and microbes and with the manipulation of the human immune response to such agents. It was suggested that the two communities should establish a regular dialogue to dis- cuss ongoing assessment and prioritization of countermea- sures, and perhaps more standardized venues for communi- cation. Topics of discussion included ways in which the expertise of the gene therapy community might be exploited in con- structing vectors, recombinant viruses and genetic vaccines that could be harnessed for biodefense applications. The group distilled out the preeminent issues that deserved attention by the gene therapy community for future devel- opment. These can largely be described as clinical applica- tions, including adaptive immunity and direct anti-infec- tives, and nonclinical applications. Much of the discussion focused on vaccine development, which is a preferred clinical application. In part, this is because the risk benefit ratio is relatively easy to calculate. The side effects of a prophylactic vaccine can be weighed against the health benefits of protection. However, in the case of a potential bioterror attack, the risk benefit calcula- tion is more complicated because it requires an estimation of the likelihood of an attack. Therapeutic vaccines might be given after an attack, so-called “post-exposure therapy,” in a strategy of ring vaccination or maybe given as a prophylac- tic in a defined population at risk—either military, civilian or both. Unlike traditional vaccines, they would need to be fast acting, but would not necessarily need to give rise to a durable immune response. They would also need to be sta- ble for stockpiling and easily transported and administered within a local arena. The flexibility of design of recombinant DNA vaccines, combined with the simplicity of their manu- facture, opens up another possible line of attack: the devel- opment of a universal “pan-vaccine” that targets an array of different bioagents. Potential advantages of such a strategy are not only logistic, but practical, as such a vaccine could conceivably protect large numbers of individuals in one administration and obviate complications that could arise if multiple vaccinations using different gene vectors were required. Adenoviruses were identified as useful vaccine vectors, although there was a clear consensus that we need addition- al study of the different adenovirus serotypes if this class of vector is to be used as a repeat administration vaccine. Fortuitously, this is already happening due to the clinical investigation of adenoviral vectors for gene therapy, pre- dominantly as anticancer agents. On the other hand, increased safety mechanisms may need to be engineered into viral agents—a concept that has arisen lately due to the development of leukemia in gene therapy patients treated with an integrating retroviral vector. Looking further ahead, the potential production of gene therapeutics needs to be evaluated with respect to the current facilities and their capacity for production purposes. It was clear that after vaccines, a major contribution of the gene therapy community could be to develop effective disease models. The ability to respond rapidly to new pathogens with informative animal models is key to devel- oping a quick working understanding of the organism and as a guide to the development of effective responses. A potential non-clinical application of gene transfer technolo- gy would be to assay for potential protective epitopes using a genetic screen rather than expensive and cumbersome pep- tide scanning. Moreover, the evaluation of many new vac- cine candidates, for example against agents such as Ebola that are difficult if not impossible for many researchers to work with directly, would also require better surrogate model systems to evaluate immune correlates. Alternatively, another approach would be to test strate- gies capable of indirect interference with pathogen growth, such as blocking of receptors or manipulation of the immune response. Various “out-of-the-box” technologies may be useful in these efforts, such as lentiviral vector-medi- ated transgenesis, delivery of siRNA and other agents or gene-based strategies that could be tested for their potential to directly inhibit pathogen growth. Finally, if the pathogen cannot be efficiently targeted directly, measures to inhibit pathogen spread to other individuals could be of value. In this regard the concept of “bioportals” was discussed; every pathogen has a preferred path of host entry to produce infection. Strategies might be developed to create blocking immunity or receptor downregulation at the portal of entry that would be sufficient to protect the population. An important consideration for any new bioterror thera- peutic is that the FDA requirements will likely be different than for standard drug development, given a very different set of priorities and the cost and risk analysis of the current threats. Therefore, the participants felt that proactive discus- sions and planning with the FDA would be necessary to identify an appropriate approach to balance safety concerns for new therapies with overall concern for safety of the pop- ulation in the context of bioterror threats. The development of a guidance document by the FDA would facilitate plan- ning by researchers in academia and biotechnology as the issues raised here for safety will relate to many different parts of the process from early development to clinical testing and application. A notable observation of the meeting was the large num- ber of nonclinical needs in bioterror defense. It was clear that the gene therapy community can provide useful tools and reagents. For example, detection of bioterror agents is an area where the expertise of biotechnology community could be exploited, and gene therapy researchers may con- tribute to this. One possibility is the engineering of living bioreporter organisms that respond to the presence of an agent with an easily monitored read-out such as color change or fluorescence. Another possibility is the creation of somatic transgenic host organisms, such as rabbits or pri- mates transduced with receptors for human specific pathogens, that could be used to study pathogen biology and potential interventions in the laboratory. Of course, there are also new challenges that the gene therapy community may face due to the nation's new focus on bioterror. Immigration policy will very likely have an impact on the recruitment of postdoctoral fellows and visit- ing researchers/postdocs from nations on the national ter- rorism list. Moreover, it is certainly within the realm of pos- sibility that the community will find itself much more under the microscope of the federal government and its various regulatory agencies. As such, the public relations challenges are an important concern. The adverse public reaction in many European countries to any kind of genetically modi- fied food is a good example of how failure to address this issue publicly and early in development can have dramatic consequences for acceptance. Another example has been the public reaction in the United States to the smallpox vaccine where issues of vaccine safety were weighed against an uncertainty about the potential of a smallpox threat to the population. Finally, the stem cell debate provides an exam- ple of how research can become entangled in political con- cerns, providing further impetus for the gene therapy com- munity to be proactive with governmental and regulatory agencies to promote their potential contribution to biode- fense efforts.