Andrzej Krauze 08/27/98
Andrzej Krauze 08/27/98
HMS Beagle's gene therapy debate, held August 24-27, 1998, covered topics ranging from somatic use of gene therapy to germ-line therapy, from the possible lack of need for gene therapy to its likely use in nearly all aspects of human health. I will summarize the debate and discuss some of the surrounding issues.
Despite semantics and anecdotal historical precedents, there was a general consensus among the participants that gene therapy is a novel form of medicine. The concept of gene therapy is simple: introduce genes whose products either can correct a defect, and thereby ameliorate the disease, or can slow the progression of a disease.
Some researchers trivialize gene therapy as a mere tool for protein delivery; as such, it is merely a new delivery technology, akin to a pump. Whatever gene therapy may turn out to be, it is generally believed that its success will depend largely on the efficacy with which genes can be delivered to the desired cell, tissue, or organ.
Nick Lemoine suggested that the term therapy is better than transfer, because this ensures regulatory and ethical consideration of clinical benefit rather than just safety. He also suggested that gene therapy will let us aim at targets against which it may take a long time to develop small-molecule drugs. Therefore the direct introduction of genes is a powerful way of producing a protein (drug) instantaneously, at the site of injection or in the circulation.
Dusty Miller commented that broader application of gene transfer to humans can involve procedures that are fundamentally different from anything previously available . These may involve, of course, modification of germ cells. These modifications might actually involve correction of a defect, repair of a mutation (in cystic fibrosis, for example), or, in some cases, enhancement of characteristics. These changes then can be passed on to succeeding generations. Of course, this is fundamentally different from any medical treatments tried previously. Therefore there is a chance that gene therapy can alleviate the problem for a sustained period of time. However, these experiments also raise the question of whether genes can be successfully introduced into the germ line without causing other kinds of problems. Thus, although gene therapy is an attractive possibility, it is still fraught with many technical difficulties.
Joe Glorioso felt that gene therapy, while not necessarily a novel form of molecular medicine, could actually be compared to a therapeutic modality of delivering proteins. He also felt that it would be important to have specific methods of delivery, particularly if the genes can be regulated in the delivery of a given protein. The idea is that gene therapy can function as a factory, producing a foreign protein in a sustained manner. This could improve the difficulties that are often experienced with direct gene delivery: bioavailability, toxicity, etc.
Although there was considerable agreement among various debaters, Paul Billings raised concerns. He felt that gene therapy may not necessarily be the best way to approach many of the diseases of the 20th century. He advocated the well-established methodology of trying to understand the nature of the disease and, in particular, trying to prevent the birth of a child with a genetic defect or other defects. Thus therapeutic intervention can be considered as a possibility, but there should be other considerations. Billings was also concerned with the cost-effectiveness of these technologies.
My own response is that while it is clear that many of these technologies are expensive, they will be just setting the stage for our future ability to introduce genes in a more economical fashion. As was pointed out during the debate, currently the treatment for adenosine deaminase deficiencies might cost up to $250,000 per year, and treatment for hemophilia may cost $100,000 per year. The introduction of genes directly, providing the protein for a sustained period of time, may be a considerably cheaper endeavor. This certainly should make it far more attractive economically.
However, the whole debate about gene transfer really hinges on the ability to introduce a gene successfully. Therefore much of the success or failure will depend on the choice of delivery system or vector. Thus the second question.
My former advisor, David Baltimore, once said that gene therapy has three problems: delivery, delivery, and delivery. In a sense, he is right, and all of us in the field are trying to find efficient methods of delivery.
At the outset, we must divide all types of delivery systems into two categories: physical methods and vectors. Physical methods include direct DNA injection, liposome formulations, and gene guns; all are methods of introducing DNA directly into the desired cell or tissue. While simple and elegant, the presently available methods are inefficient and often express the foreign gene only transiently.
Most investigators have therefore relied on the use of biological vectors, which are mostly viral, including retroviral, lentiviral, adeno-associated, adenoviral, and herpesviral vectors. Each vector has major limitations: inability to infect nondividing cells (retroviral), adverse immunologic consequences (adenoviral), cytotoxic consequences (herpesviral), and a limited range of foreign genetic material (adeno-associated). The ideal vector will be able to be generated at high titers (>109 IU/mL), easy to make, and capable of integration and regulated transcription of the gene, with no immunologic consequences. Improving the vectors for efficient and safe gene delivery remains a major challenge. This effort will now need to include regulated gene expression.
The methods that have been used and described here have now been quite extensively tested, and nearly 6,000 patients are enrolled in almost 300 clinical trials worldwide. Yet there has been no real successful example. Part of this has to do with the fact that the vectors that were used do not allow long-term production of the protein and part that many of the trials are really designed to determine safety rather than efficacy. A large number of trials are in cancer patients, where there is the additional problem of inability to follow the patient because of the terminal nature of the disease. Thus the experience from clinical trials is mixed.
Nevertheless, one could come to certain principles, and the methodology of clinical trials has been established. The protocols are well established, the informed consents are well established, and patient participation is well established. At issue really is the methodology of introduction of the genes. Thus the emphasis in the coming years will be strictly on making vectors that are highly efficient at delivering genes in a tissue-specific manner. Therefore there is good reason to believe that gene therapy will succeed.
It is also felt that, to succeed in gene therapy, one still has to do much more basic science - particularly in generating appropriate safe and regulated vectors as well as in the areas of immunologic consequences and the nature of the cell biology of the system. Clearly the immune system will remain a big problem, because many people who have never seen the gene product may actually modulate an immune response. This consideration may require better vectors for fighting the immune system.
This question remains open. Clearly, gene therapy will be able to influence the outcome of genetic defects, because lack of the gene product can be complemented by introduction of the foreign gene capable of making that protein. In some cases, it will be possible to augment the endogenous levels of a protein. In the case of cancer, gene therapy offers the hope of boosting the immune system by introducing lymphokines, cytokines in tumor cells, so that they are recognized as foreign cells and destroyed by the body's immune system. In other cases, lethal drugs can be introduced.
Genes can be targeted to specific cells by modifying the vector. The ability to selectively introduce genes in a tissue will allow introduction of genes in the central nervous system, hematopoietic cells, etc. Although much of the current pursuit is in the area of somatic-cell therapy, people will soon attempt in utero and perhaps even germ-line gene therapy.
Aside from the ethical issues related to germ-line gene therapy, there are significant technical issues before it can be used. Nevertheless, the technology is moving very rapidly, and society should be prepared to cope with it. A healthy dialogue between practitioners of this art, end users, and ethicists will be beneficial to all.
Finally, serious legal and ethical questions will need to be discussed. For example, if some people infected with a virus actually turn out to make a recombinant virus that causes a disease, this will be of great concern. There is also the question of who will be responsible: the inventors or the company doing the experiments or providing the gene therapy as a drug? Someone may jump the gun and try to do the experiments, which will cause a problem for the rest of the field.
There is also the issue of whether the biological activity of certain proteins may interfere with their ability to function once introduced by a virus, as opposed to being introduced directly into the cell. For example, patients who can now tolerate factor IX protein may not be able to do so if they make antibodies against factor IX that is being continuously produced by gene therapy. These are theoretical problems, but they are worth considering.
Overall, there is still a substantial degree of concern regarding the use and safety of these methods. This needs to be addressed, and the process of patient education, consent forms, and other issues should be addressed now. Gene therapy is here to stay, and society has to learn to adopt it as a new medical opportunity.
Inder Verma, moderator, is currently American Cancer Society Professor of Molecular Biology, chair of the laboratory of genetics at theSalk Institute for Biological Studies, and adjunct professor in the Department of Biology, University of California at San Diego. He received his Ph.D. in biochemistry from the Weizmann Institute of Science, Rehovot, Israel, in 1971; and was a postdoctoral fellow (with David Baltimore) in the Department of Biology, Massachusetts Institute of Technology, from 1971 to 1974. He is a member of the NIH Recombinant DNA Activities Committee and former chair of the ad hoc review committee, and serves on several other scientific advisory boards. He serves as an editor of Gene, Gene Expression, and the Journal of Virology. His major fields of interest are molecular analysis of oncoproteins, Mos, Fos, Jun and NF-kappa-B/Rel, and suppressor genes BRCA1/2; gene therapy involving retroviral, adenoviral, AAV vectors, and generation of novel lentiviral vectors; and hemophilia B model systems.
Paul Richard Billings is currently chief medical officer and deputy network director of the Heart of Texas Veterans Integrated Service Network. A board-certified internist and medical geneticist, he received his M.D. and Ph.D. degrees from Harvard University. His research has encompassed molecular, cellular, and social aspects of genetics.
Ronald Cole-Turner is the H. Parker Sharp Associate Professor of Theology and Ethics at Pittsburgh Theological Seminary. He is an ordained minister of the United Church of Christ, for which he chairs the committee on genetics. He is a member of the advisory board of the John Templeton Foundation, and serves on the advisory board (executive committee) of the Program of Dialogue Between Science and Religion of the American Association for the Advancement of Science. He is the author of The New Genesis: Theology and the Genetic Revolution (1993) and coauthor of Pastoral Genetics: Theology and Care at the Beginning of Life (1996), which was awarded a 1997 Prize for Outstanding Books in Theology and the Natural Sciences by the John Templeton Foundation and the Center for Theology and the Natural Sciences. He is the editor of Human Cloning: Religious Responses (1997).
Joseph C. Glorioso III is the William S. McEllroy Professor of Biochemistry and chairman of the Department of Molecular Genetics and Biochemistry at the University of Pittsburgh School of Medicine. He is director of the Pittsburgh Human Gene Therapy Center, a founding board member and treasurer of the American Society of Gene Therapy, president-elect of the Association of Medical School Microbiology and Immunology Chairs, and the U.S. editor for the journalGene Therapy. He received his Ph.D. in microbiology from Louisiana State University. His main research interest is the development of herpesvirus vectors for human gene therapy applications.
Nicholas R. Lemoine is the European editor of the journal Gene Therapy. He is director of the Imperial Cancer Research Fund Molecular Oncology Unit at Hammersmith Hospital and professor of molecular pathology at Imperial College School of Science, Medicine, and Technology (both in London), where he leads the cancer gene therapy program. His particular interest is in targeted gene delivery/expression and genetic vaccination.
A. Dusty Miller is a member of the Fred Hutchinson Cancer Research Center and an affiliate professor at the University of Washington (both in Seattle, Washington). He received his Ph.D. in pharmacology from Stanford University. He has served on the Recombinant DNA Advisory Committee and has been an associate editor for the journal Human Gene Therapy. Currently he serves on the editorial boards of several other scientific journals. His main research interests are basic virology and gene therapy. He constructed the retroviral vectors used in the first human clinical trials of gene marking and gene therapy, and his retrovirus-production systems are in wide use.
Jude Samulski's primary expertise is in the area of molecular virology. He received his Ph.D. in the Department of Immunology and Medical Microbiology at the University of Florida, where he generated the first infectious clone of the human parvovirus adeno-associated virus (AAV). Postdoctoral training under Thomas Shenk at Princeton University resulted in the development of AAV vectors and packaging cell lines, initiating efforts to test this nonpathogenic virus as a human viral vector for gene therapy. As a member of the NIH Recombinant DNA Advisory Committee, he has participated in the review of protocols related to DNA delivery in humans.
Currently he serves as director of theGene Therapy Center at the University of North Carolina at Chapel Hill, where he has continued investigating the molecular biology of AAV and its potential use as a delivery system for the correction of human genetic diseases.