H U M A N G E N E T H E R A P Y 1:371-372 (1990) Mary Ann Liebert, Inc., Publishers

EDITORIAL September 14,1990: The Beginning On September 14, 1990, at 12:52 pm, a 4-year-old girl with adenosine deaminase (ADA) deficiency received an infusion of autologous T cells into which a normal A D A gene had been inserted. The procedure took place in the Pediatric Intensive Care Unit of the Clinical Center of the National Institutes of Health; she received a billion cells; the infusion took 28 minutes; the entire undertaking was clinically uneventful. A n d so began human gene therapy. The event itself—the intravenous infusion of blood cells—was routine by hospital standards. So routine, in fact, that the child, w h o has experienced many needles in her short life and expected something special to happen this time, just played in her bed throughout the infusion. W h e n it was over, she was still waiting for something out of the ordinary to occur. N o w that gene therapy has begun, let us address several relevant questions. W h y has this clinical protocol generated so much public interest and scientific debate? W h y was this particular gene therapy protocol the first one approved? What are its potential risks? What are its potential benefits? T o begin with, the procedure carried out on September 14 was not a medical "breakthrough," despite the enthusiastic press reports. From a medical and scientific viewpoint, most of what transpired on that day was based on what had been learned years before. What generated the interest and controversy, I believe, was that the event resulted in a cultural breakthrough. A cultural breakthrough is a specific event that changes the way that w e as a society view ourselves or h o w w e do things. Even though gene therapy has been discussed and debated for years as a potential new way to treat disease and the A D A gene therapy protocol itself had been publicly reviewed for 3Vi years, society was taken by surprise when the protocol actually began. T o review the extensive history of the A D A protocol: It was submitted for review in its original form on April 24, 1987. After a dozen formal written reviews (all critical but constructive) an extensive public discussion took place at a meeting of the H u m a n Gene Therapy Subcommittee on December 7, 1987. Six months later, on June 10,1988, a separate human gene transfer clinical protocol (the N2-TIL study, see H u m . Gene Ther. 1,73-85) was submitted for review. This latter protocol was viewed as a way of getting a "running start" for a true gene therapy protocol. The gene transfer protocol was reviewed by seven different regulatory committees over a 6-month period with greater than 26 hours of formal proceedings, much of it held in public with the press in attendance. The initial gene transfer experiment began on M a y 22,1989, amid considerable press coverage. The present revised A D A gene therapy protocol (Hum. Gene Ther. 1, 327-362), submitted February 23,1990, has had continual press coverage throughout its lengthy review process. A n d yet, in spite of all this media attention, a considerable portion ofthe public, including large segments ofthe medical and scientific communities, did not really believe that an approved clinical attempt at gene therapy was going to take place for, perhaps, years. After the protocol was initiated and the gene-corrected cells were infused into the patient, the question w e were asked over and over was: H o w did this happen so unexpectedly? The answer is that society had simply not come to terms with the concept that genetic engineering was ready to begin. Only time will tell if September 14 was an importantfirststep or a false start in the history of gene therapy. But if September 14 retains its importance, it will be due in part to the public's sudden realization that gene 371

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therapy, i.e., the genetic engineering of human cells, has become a reality. Even if this initial experiment does not fully succeed, public awareness and tentative acceptance n o w exist. But, of course, therein lies the cause for some of the controversy. For thisfirstexperiment is n o w in the spotlight. The promises, the hopes, the expectations of cures are all laid before the public. If the initial protocols fail badly, then the public might descend with a vengeance on the false prophets. A n understandable criticism leveled by some of our colleagues is that w e should have waited until w e were more certain of success. Just one more year m a y have provided greater confidence that the initial protocols would work. Granted that the protocols m a y be safe for the patients, but are they "safe" for the field of gene therapy? Considering h o w emotionally volatile the subject of h u m a n genetic engineering is, if no patient is helped (or, worse, if patients are indeed harmed), then negative public reaction might very well set back the whole field of gene therapy. Should w e have waited? M y personal reasons for pushing forward were contained in an earlier editorial (Hum. Gene Ther. 1, 109-110). But only the future will determine if w e should have waited. If September 14 marks the beginning of successful gene therapy treatments . . then w e were right not to delay. If patients are harmed and a public backlash occurs . . . then w e were wrong. I believe that w e were right. The other questions listed above can be answered briefly because the extensive discussions of the H u m a n Gene Therapy Subcommittee and the full Recombinant D N A Advisory Committee have addressed each of them in detail. The Minutes of those meetings are published here in H u m a n Gene Therapy as they become available (see 1, 363-370, 481-501). W h y was A D A deficiency chosen for the initial h u m a n gene therapy clinical protocol? Because there are several features of this disease that make it particularly applicable as a gene therapy candidate (Hum. Gene Ther. 1,340-348). Perhaps the most important is that A D A deficiency is one ofthe few diseases k n o w n where gene-corrected cells should have a selective growth advantage in the patient's body. W h a t are the potential risks? There are two categories ofrisk.First there are the clinical risks associated with any cell infusion: infection, chills, fever, etc. In a modern hospital with good blood banking procedures and competent medical and nursing care, these risks are low. Second there are the risks associated with the gene transfer procedure itself. The possibility of inadvertently producing an infectious virus that could harm the patient and the public has been reduced to near zero. W h a t remains as a finite risk, however, is the potential for inducing a cancer. The vector carrying the new gene is integrated randomly into the genome. This means that there is a theoretical possibility that vector insertion m a y activate an oncogene or inactivate a tumor suppressor gene. Cancer is a multistep process, and an activated oncogene would be but one step along the oncogenic pathway. It would be, however, one step. Extensive safety studies have been carried out over the past 5 years in animals (mice and primates) and not a single vector-containing tumor has yet been found. Nonetheless, the finite possibility of a cancer caused in part by the gene transfer procedure exists. This risk must be balanced against the potential benefits. W h a t are the potential benefits? The primary benefit for the ADA-deficient patients would be to restore their immune system to normal, thereby eliminating the threat that they n o w face of succumbing to a lethal infection. In addition, since patients with an impaired immune system have an increased risk of developing cancer, an improved i m m u n e system would reduce the possibility of a malignancy. In approving the A D A gene therapy clinical protocol, all the regulatory committees concluded that the potential benefits outweighed the potential risks. With the initiation ofthe A D A protocol, our society is n o w beginning to adjust to the n e w reality of genetic engineering. Although it will be a number of years before gene therapy will have any significant impact on the lives of most people, the technique does have the potential for accomplishing immense good by reducing the suffering and death caused by disease. W e can look forward to the time when, with proper safeguards imposed by society, this important n e w therapeutic procedure becomes widely available. Dr. W . French Anderson Editor-in-Chief 372

September 14, 1990: the beginning.

H U M A N G E N E T H E R A P Y 1:371-372 (1990) Mary Ann Liebert, Inc., Publishers EDITORIAL September 14,1990: The Beginning On September 14, 1990,...
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