Pioneer James Wilson Reflects On Gene Therapy's Hopes, Hype

Hype Editor's Note: In late 1990, the first gene therapy was administered to a young patient with the hopes of correcting a defective gene that normally produces adenosine deaminase, a key immune-system enzyme. In the more than five years since then, gene therapy has grown in scope and notoriety. To date, in excess of 100 gene therapy trials-involving nearly 600 patients and dozens of diseases, including some types of cancer-are under way. Despite this multimillion-dollar effort and the much-hyped promise that gene therapies may hold for patients, many in the biomedical research community assert that gene therapy, now fully into its sixth year, is still cutting its teeth. FOCUS ON FUNDAMENTALS: "I expect a fairly productive era, primarily focused on basic research," predicts the University of Pennsylvania's James Wilson. A major figure to emerge among gene therapy researchers is James Wilson, director of the University of Pennsylvania Medical Center's three-year-old Institute for Human Gene Therapy. Wilson is best known for leading the research teams that developed gene-replacement therapies to treat cystic fibrosis and familial hypercholesterolemia. Recently, associate editor Karen Young Kreeger met with Wilson on the Penn campus for a wide-ranging discussion of his views and outlook for this burgeoning and highly charged field. Q How do you think some of the early enthusiastic expectations for gene therapy, especially those that have been extolled in the scientific media and the general press, have either hurt or helped gene therapy research? A I think that we, as a field, have not articulated well the true goals and expectations of some of the human trials. There are many that are responsible for that. The investigators and others involved in the field have to share some of the fault. But, the reality is that this is so very early. As far as I'm concerned, [a trial] is successful if it's informative and, quite frankly, a lot of the trials have not been that informative. And, if we haven't learned anything, then I would question, in many situations, whether they were useful or not. Q Some detractors of research in the field point out that, despite all of the effort put forth in gene therapy in the last five years, there is no incontrovertible evidence that gene therapy has cured or even helped one person. How would you respond to such criticisms? A I would say that if the goal is to prove that a therapy is truly effective from the clinical standpoint, then it's going to require a substantial effort-large, well-controlled trials. That is not what has occurred in the field of gene therapy [in the major trials that have been conducted to date]. We have not been effective in articulating what the goals of these trials ought to be. Let me give you an example. Let's say there's a new vector system [genetic material used to introduce specific genes into an organism's genome] that has been developed in animal models, and it looks extremely interesting, and that vector system is tested in a human pilot experiment in a very objective, critical way. In that trial, we learn that it has substantial flaws that were not predicted from the animal studies. That's an extremely successful trial, because it will enable us to redirect our resources and our efforts towards modifying that vector or utilizing other vector systems. Did that cure a disease? No, it didn't cure a disease. Was it successful? Yes, it was successful. So, I guess it's the way in which, scientifically, you view the word "success." Q You've stated that improvement of a patient's health should be the benchmark for judging a gene therapy. Obviously, that is the most important objective, but are there other benchmarks for assessing the success of a clinical trial? A The key here is that we minimize the risk to patients, but that we learn as much as we can about the potential of the model that we're testing. I think the lesson in Phase I trials is that we try to build into those trials components which assess what I call biological efficacy; that is: Have we transferred the gene? Is it expressed? How efficiently is it expressed? In what cells is it expressed? How long is it expressed? What is the host response to that? Now, if you could learn from all of those questions in a clinical trial, that would be very successful. Q But how realistic is it to expect to learn all of that from one clinical trial? A You should strive to learn as much as you can, and if you're not going to learn more about the ultimate utility of the therapy, then I would question whether it's useful or not. If we can address and challenge some of these concepts early in the field, we may be able to redirect ourselves towards a more effective use of resources. I think that's also going to be important because there's going to be a limited pot of money to support this research. Q In early December, the National Institutes of Health released its much-anticipated "Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy." The committee of experts who authored the report recommended that clinical trials need to be reassessed with an eye toward emphasizing basic science more strongly. What's your view in this area? A My view on clinical trials is that they should be done, but they need to be done in the context of a good science infrastructure. The point is you cannot uncouple clinical trials from basic research. They have to be done in the context of basic research and reflect back on it. Not all clinical trials are structured in that way, and some are not performed by investigators that are well-grounded in basic research. Q The report has a number of suggestions on how to review gene therapy research. One of them recommends against creating an NIH gene therapy study section. How do you feel about that? A I agree entirely with not having a dedicated study section for gene therapy. I would have concerns that there may be two standards if there was a designated study section. My point of view is that funding for gene therapy, especially if we define it broadly, should be driven by the traditional disciplines and study sections. If you restrict it to one study section, there could be the accusation that that study section has a different standard for the quality of science than other study sections. Furthermore, I think gene therapy is going to infiltrate so much of our medical research that if you just restrict it to one study section, you're actually going to limit the funding that's going to go to gene therapy. Gene therapy ought to be considered a tool, an important rationale for funding basic research in virology, immunology, stem cell biology, and transplantation, for example. So, I think it's a bad idea to have a dedicated study section, and I'm glad that the report suggested that. Q As a result of gene therapy research moving very quickly, some have questioned the scientific rigor or benefit of some clinical trials or other studies. Do you agree with that? If so, do you think that some of this is because there is pressure from funding agencies, patient groups, university officials, and biotech firms to rush forward with gene therapy studies? A I think in the aggregate it has been useful to the field and useful to the public to bring gene therapy forward into human clinical trials. Until it had, [gene therapy] was rather an abstract concept, and was difficult to develop in terms of policy issues. The regulations [governing human gene therapy clinical trials] really didn't exist until people began to consider, if not implement, clinical trials. In that enthusiasm, though, I think that other pressures were brought to bear to move clinical trials forward in a way in which the incremental gain to the field was very little. It was issues of recognition-one very easy way to [establish] yourself, your institution, or your company was to have a RAC [Recombinant DNA Advisory Committee]-approved trial. So, for a while, a RAC-approved clinical trial made an institution or a company a player in a field for which there was a lot of interest. I think that did create incentives for people to participate prematurely. But I think that's changed to a certain extent. Q Researchers and NIH officials alike have stated that gene therapy research needs to be reevaluated, but they have also said that, in time, it would revolutionize medicine. Are these contradictory messages? A I don't think the message is necessarily mixed. The [NIH] report is grounded on the assessment that gene therapy is valid and it will be important to medicine. This is especially important to a field that has started from basically zero in the mid- to late '80s to the tremendous focus that has been placed on it in such a short period of time, and was not developed in the context of any strategic plan. One can always reflect retrospectively on how it evolved in this flurry, which they did. They did point out some of the issues that the field ought to be aware of in the future, and that is the nature of clinical trials. Q A substantial portion of gene therapy trials are backed by industry. In the haste, as some have put it, to commercialize therapies in a very young field, some critics have charged that an over-reliance on commercial involvement has moved the focus of gene therapy research away from rare diseases to diseases that affect more people, because biotech companies are looking for a quick return on their investment. First, in your experience, is this so? And secondly, is the expansion into cancer- and AIDS-related gene therapy research necessarily a bad development for the field as a whole? A I think it would be extremely regrettable for the field to rely entirely on industry for a substantial part of its development. Industry has to be market-driven, and especially the biotech industry is going to view this in the very short term. The disease targets that are selected for investment have to fulfill the corporate formula involving size of market, proprietary position, and a lot of other issues. The reality is that the clinical models that will be the most discriminating for testing fundamental concepts may not fit the corporate formula. As an academic-based community, it's been my belief that we should partner with industry when appropriate, but not rely on industry, so that we can continue to seek out the best and most discriminating models to test the validity of the basic concepts of gene therapy. Often, though, the models for which the market is the greatest and the profit is the greatest are not necessarily the simplest. Cancer is one of them. Cancer is a very complex disease to consider as a target for gene therapy. What I've tried to accomplish at Penn, as well as tried to articulate [at NIH] is to develop mutually beneficial relationships with industry and to promote them, but not rely on them. Q Where do you think gene therapy is heading in the next five years? A In many ways, the field has just begun. I expect a fairly productive era, primarily focused on basic research. An area for which a tremendous amount of progress has been made, but much more needs to be accomplished, is in developing vectors. The vectors are the enabling technology of this field. We've only explored a few different versions, which are primarily based on viruses. There are many, many more strategies that could be pursued. And, as we make progress in this area, the real potential in multiple other areas will expand dramatically. In addition, there will continue to be a focused testing of some of these concepts in human trials. My hope is that this can occur in a way that is useful and informative to the basic research component of the field, so that if we haven't developed something that will be useful, we can learn why it isn't and how to make it better.

Pioneer James Wilson Reflects On Gene Therapy's Hopes, Hype

Interested in reading more?

Become a Member of