Changing Roles for Academia and Industry in Genetics and Gene Therapy
Authors: Theodore Friedmann
Journal: Molecular Therapy (2000)

A recent editorial proposes that commercial interests are producing an increasing opacity in the field of human gene therapy (1Nature. 1999; 402: 107Crossref Scopus (3) Google Scholar). The grounds offered for this pessimistic assertion are the recent revelation of patient deaths and a growing awareness of morbidity in a number of gene therapy clinical trials, a perceived loosening of public scrutiny over clinical gene therapy studies, and a growing presence of commercial interests in those studies. However, just the opposite is true. It has been all too easy for some observers recently to ascribe these problems to the role of industry in current gene therapy studies. It is, of course, far more complex than that. Although the field of human gene therapy grows vastly more complex as a result of rapid technical advances, expanded clinical trials, and burgeoning interactions between academic and commercial centers, we are coming to appreciate more clearly than ever, perhaps slowly and sometimes through misfortune, the many technical hurdles and the difficult ethical and public policy issues that still face human gene therapy, including the factors that influence the relationship between academic investigators and corporate partners. During the initial phase of the development of human gene therapy, translation of basic concepts into clinical reality seemed relatively straightforward and largely within the basic and clinical research capabilities of academic gene therapy centers. Even when the logistical difficulties of vector production emerged in early clinical studies, it seemed likely that a division of labor between academia and industry would eventually develop. Academia would innovate and provide the basic underpinnings for the technologies of gene transfer and gene delivery while industry would implement and translate basic knowledge into clinical reality, largely through the production and distribution of gene transfer vectors. This model appeared to have support during the late 1980s to mid 1990s, when academic centers in several institutions established programs not only to develop the basic molecular genetic and cell biology infrastructure required for human application but also to design and carry out clinical studies. However, with the beginning of active human clinical studies in the late 1980s and early 1990s, it became increasingly clear that this emerging field of medicine would not fit easily into this simplistic model. Of course, because of the scientific groundwork being laid out in academia and the existence in academic medical centers of the clinical resources necessary for clinical studies, it was obvious that implementation of clinical studies would require the very heavy participation of the academic centers. However, at the same time, it also became clear that the difficulties and prohibitively high costs of performing clinical studies, especially producing and testing clinical-grade vectors, would keep clinical gene therapy studies out of reach for most academic investigators. Clinical studies would require new kinds of collaborations. Attempts to ameliorate these continuing problems have come from several directions. Many investigators have developed commercial liaisons, several in the form of research collaborations with established biotechnology and pharmaceutical firms. Many of these interactions have been structured not as broad long-range programs to attack the basic technical and conceptual problems that still hamper clinically useful gene therapy, but rather as limited project-specific and short-term research collaborations or material transfer agreements to provide reagents not available or affordable in academic settings. Many other collaborations took the form of new biotechnology start-up companies that were compelled by commercial realities, even more than the large pharmaceutical and biotechnology firms, to limit their efforts to shortrange goals and vector production or other material transfer. A second mechanism for facilitating clinical studies in the United States came through the establishment in 1994 of the National Gene Vector Laboratories (NGVL) funded by the National Center for Research Resources (NCRR) of the National Institutes of Health. Although these core production laboratories have been able to provide valuable and high-quality clinical-grade vectors to a very limited number of NIH-sponsored academic investigators, they were not designed to support the expensive preclinical toxicology studies required for human studies. This placed the burden on investigators to seek support for many aspects of their studies from an unaccustomed source, i.e., industry. Furthermore, because the NGVL program is inaccessible not only to most academic clinical scientists but also to all industrial investigators who wish to undertake clinical studies, its role in producing clinical-grade vectors for human trials has been largely assumed by a growing number of alternative good manufacturing practice (GMP) production facilities. These facilities include several entirely commercial sources, including a rapidly growing number of GMP production facilities based at and partially supported by academic institutions and at least one chimeric, joint academic–industrial partnership, the one in La Jolla between the University of California San Diego and Roche, that is an entirely forprofit facility based at an academic institution but only loosely connected to the genetics and gene therapy programs of the university. The traditional distinctions between the scientific roles of the academic and industrial worlds in innovating gene therapy techniques and instituting clinical studies have therefore become heavily intertwined and interdependent. This is strikingly exemplified by a recent symposium sponsored by Nature Biotechnology and supported by a pharmaceutical firm. The meeting, entitled “Gene Therapy: Delivering the Medicines of the 21st Century,” included the expected presentations on basic issues of gene delivery and expression, preclinical and clinical applications, and the design of future infrastructures for clinical gene therapy. Not only were many of the basic science presentations made by biotechnology firms or by academic investigators with major biotechnology collaboration, but also the majority of the preclinical and clinical discussions and all three presentations on future strategies for clinical implementation of gene therapy were given by representatives of industry and the investment community. This kind of meeting organization is increasingly common. The growing presence of industry in such symposia reflects the major contributions that industry is making to the concepts and tools of the field and to its role in catalyzing many of more than 300 clinical gene therapy studies currently underway throughout the world. The experience to date with clinical gene therapy trials makes clear that the next phase in the development of truly efficient methods for gene therapy will require new generations of concepts and tools. Such new resources will require efforts in basic and translational research that will be too broad and too expensive for either academia or industry to undertake alone. It is therefore vital that intensified and broadened basic and translational research collaborations and developmental programs be established between academia and industry to take advantage of their mutually complementary strengths, i.e., the innovation and clinical resources of academic centers and the translational and applied research, problem-solving, the scale-up capabilities and “get-it-done” mentality, and the deep financial resources of industry. The path to these liaisons will be complex and not without costs. Academic institutions have not always succeeded in separating the potential advantages of close goal-directed translational research collaborations with industry from the real and perceived challenges posed by such partnerships to their academic mission nor in devising smooth technology transfer mechanisms for facilitating industrial relationships while protecting the intellectual property interests of the university and its faculty. On the other hand, although the biotechnology and pharmaceutical industries have produced far better structures than academia for translating biomedical advances into practical reality, they often have been unwilling or unable to commit resources sufficient to establish true intellectual partnerships and vigorous far-ranging research programs with academic institutions. Fortunately, the role of industry in recent overall gene therapy efforts has expanded markedly to include powerful and productive basic research to augment their applied and translational research efforts. The potential for great economic benefits to investigators, companies, and investors from genetic research has undoubtedly influenced some aspects of the design and implementation of clinical studies, including the choice of clinical disease targets, the design of the protocols, and even some conflicting approaches to protocol submission and the review and reporting of untoward clinical outcomes. Some diseases have been chosen for their potential economic return, but of course in most cases these models correspond to diseases with the greatest societal impact—cancer, cardiovascular disease, neurological disease, AIDS, etc. In other cases, far less common diseases have been selected for their potential to illuminate mechanisms of gene delivery and pathophysiology. The recent tragic death of a patient in one such clinical gene therapy study for ornithine transcarbamylase (OTC) deficiency and growing evidence for adverse outcomes in a number of other cancer and cardiac studies have added significant weight to the potential problems associated with economic influences on medical decision-making. In that regard, the nascent field of gene therapy is probably not different from many other areas of experimental medicine and, one might argue, is even less prone to some of these difficulties because of the high visibility and resulting extensive oversight that characterizes the field. Nevertheless, it would be a great mistake to ignore these real complexities and potential problems in the pursuit of human gene therapy. It would be an equally great mistake to conclude that they are unique to this field or biomedicine or that they bring into question the undoubted correctness of the concepts of gene therapy and its ultimate promise to ameliorate a great deal of suffering. Because the worlds of academia and industry will continue to play indispensable roles in the field of gene therapy and because they are becoming increasingly interdependent, it is important for them both to formalize their overlapping roles in more collaborative efforts. This would be in keeping with recommendations in the 1995 report to the NIH director of the advisory committee chaired by Stuart Orkin and Arno Motulsky. The committee's report emphasized the need for the field of gene therapy to make fewer undeliverable promises for quick cures, to do more rigorous clinical research, and to establish more effective interactions with industry. We are witnessing the beginnings of an explosion of opportunities for these kinds of meaningful and productive collaborations in the broad field of human genetics aimed at fostering greater interactions and synergies to make optimal use of the mass of information already pouring from the cornucopia of gene discovery, genomics, and gene therapy. Research advances in genetics in the “postgenomics” and “functional genomics” eras cannot stop with gene discovery and with the elucidation of mechanism, but must be translated quickly and efficiently into gene-based therapies. To travel down that road, it will be necessary for universities and research institutions to solve more of the administrative problems and bureaucratic tangles that are often placed in the way of industrial collaborations. It will also be necessary for industry to look past the immediate short-term promises of a new technique and forge truly effective intellectual alliances with academic partners. One does not have to be a self-delusionary Pollyanna to see enormous good at the end of such a trip. There are no biomedical research and development opportunities more thrilling than those being presented to us by the modern world of genetics, and imaginative partnerships between academia and industry will undoubtedly help to bring the promise to fruition.