- Email: [email protected]
A Decade of Accomplishments: Gene Therapy and the ASGT
commentary
© The American Society of Gene Therapy
A Decade of Accomplishments: Gene Therapy and the ASGT Theodore Friedmann1 doi:10.1038/sj.mt.6300284
T
his year we celebrate the tenth anniversary of the annual meetings of the American Society of Gene Therapy (ASGT), marking what many feel has been the maturation of the field of gene therapy from promise to incontrovertible therapeutic benefit for people with otherwise intractable disease. One needs only to reflect on where the field was at the time of the first annual meeting a short decade ago to appreciate the great changes that have taken place and the role that ASGT has played in bringing this new form of medicine to clinical reality. A decade ago, the gene therapy community was still coming to grips with the reality that, against all of our rosiest expectations, while we had certainly established a significant body of basic science and animal modeling, we had not yet achieved either convincing demonstration of efficient and stable gene transfer or any evidence of significant therapeutic benefit, to any patient in any of the early clinical studies. We had begun to appreciate that our expectations in those early studies far exceeded our grasp both technically and medically, and that most us had been too optimistic with regard to the apparent simplicity of the concept of gene therapy. Clearly gene therapy needed a new approach to create clinical reality from the conceptual and scientific foundation that had emerged earlier. With some pointed skepticism from some other areas of the scientific and public policy communities and the media, and particularly at the urging of the director of the National InDepartment of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California, USA. Correspondence: Theodore Friedmann, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California 92093, USA. E-mail: [email protected] 1
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stitutes of Health (NIH), the gene therapy community was beginning to appreciate the need to develop more rigorous basic and clinical research underpinnings for our field. It occurred to a few of us that a far greater degree of interaction among investigators would help to set appropriate directions for the field. As is often the case, such a task falls on the shoulders of one inspired and inspiring leader. In our case, that person was George Stamatoyannopoulos (Figure 1), who emerged as the principal architect of this new structure; he agitated, urged, cajoled, and browbeat us as only George can do, shaped us into the ASGT, and then quickly became the Society’s first president. No single person has poured as much of his time and effort into the formation and workings of this Society, and the organization’s success is due in no small measure to his service. It is for that reason that the ASGT honored George this year in Seattle—where these meetings began—with a special presidential medal. The growth and development of the Society also owes an enormous debt of gratitude to the long list of Society officers and succeeding presidents: Jim Wilson, Savio Woo, Inder Verma, Malcolm Brenner, Joe Glorioso, Don Kohn, Kathy High, and Mark Kay (Figure 2). Of course, anyone who has ever chaired a committee or served as president of an organization knows that it is the staff that really carries organizations forward and does all the heavy work. The ASGT is no different, and I would like to acknowledge the present Society staff: Ken Jawoski, Mary Dean, Nadine Kikkonen, and Liz Dooley. I want to say a special word about the ASGT’s executive director, Liz Dooley. Liz recently announced that she was having trouble deciding whether she should stay with the Society or go ahead with her
plans to marry a very fortunate man in Boston. Apparently, all our pleading, coaxing, and even dire threats were not powerful enough to force her to stay with us, and we wish her and her new husband happiness and good fortune. One of the major achievements of the Society over the past decade has been the establishment of the journal Molecular Therapy. The journal has become an exceptionally influential and important voice for the field of gene therapy, in large part as a result of the standards of excellence and rigor that were established by the founding editor, Inder Verma—standards that are now so effectively being further developed by the current editorin-chief, David Williams, and the editor, Rob Frederickson. We thank Inder for setting the bar so high and getting the journal off to such a fine start. A year ago ASGT set a number of goals for the following year. These included the initiation of a discussion with the NIH on ways to catalyze progress in gene therapy and other areas of clinical translation; the facilitation of the move of Molecular Therapy to a new publisher, Nature Publishing Group; the fostering of increased interaction and cooperation with other professional societies in gene therapy and related fields; and the strengthening of the Society’s fiscal health in several ways, including the establishment of an endowment. The ASGT leadership identified major areas that were considered obstacles to more rapid progress in clinical applications of gene therapy. These areas included the paucity of funding to cover the huge costs of clinical trials, the difficulty for many investigators of obtaining ready access to clinical-grade gene transfer vectors and other reagents, and the cumbersome funding process for clinical studies. Although we applaud the NIH road map for its emphasis on translational research, we also recognize that clinical applications in gene therapy and other areas of clinical research are struggling with support structures that are not ideally serving the overall clinical research effort in the United States. In the case of vector production and access, some years ago the NIH very wisely created the National Gene Vector Laboratory (NGVL) Program with especially
www.moleculartherapy.org vol. 15 no. 9 september 2007
© The American Society of Gene Therapy
Figure 1 George Stamatoyannopoulos, founding president of the ASGT.
generous support from the National Center for Research Resources, the National Heart, Lung, and Blood Institute, the National Cancer Institute, the National Institute for Diabetes and Digestive and Kidney Diseases, and other NIH institutes. The newly elected vice president of the Society, Ken Cornetta, served as coordinating director of the program, which went on to provide a total of 53 varied clinical-grade vectors used in 37 clinical gene therapy clinical trials involving many hundreds of subjects. In fall 2006 the ASGT proposed to the NIH leadership a dual plan to facilitate and catalyze additional clinical trials. The first recommendation from ASGT was that the NIH continue the valuable NGVL program. To our very great disappointment, the NIH has decided to replace the program with a coordinated vector-production program that will make use of some of the existing NGVL facilities to provide toxicological and preclinical resources and production facilities specifically for lentivirus and adeno-associated viral vector systems. Although this new vector production strategy will certainly facilitate a selected set of clinical trials, it will likely compromise innovation in the development and clinical application of other vector systems. A second recommendation to the NIH was aimed at the development of a more seamless funding structure for supporting clinical trials, and this concept is receiving evaluation by NIH leadership. We strongly urge the NIH leaders to Molecular Therapy vol. 15 no. 9 september 2007
commentary
continue working with ASGT to incorporate this or similar strategies into their translational efforts to facilitate clinical studies in both gene therapy and other areas of clinical research by making the grant-support process for clinical research even more seamless and efficient. Several other goals that we set for the year have had somewhat smoother sailing. The move of the journal to Nature Publishing Group, under the leadership of David Williams and the ASGT publications committee chaired by George Stamatoyannopoulos, has gone well, ensuring that the journal retains its position as the preeminent journal in the field. Similarly, the Society is in discussion with the international gene therapy community to develop more effective international interactions and collaborations. Finally, the ASGT has established an endowment fund and has already received an initial anonymous donation. The Society is now developing plans for fundraising to increase its endowment to ensure its long-term financial health. We certainly welcome your contributions—great and small; personal, academic, and corporate. Finally, a few general comments are in order about the public and scientific image of the field of gene therapy. Science is some-
times portrayed to the public in very confusing and misleading ways, by both scientists and the media. The publication of an early draft of the human genome, including the discovery that there were fewer genes than expected, was greeted by this hilarious headline in a major U.S. West Coast newspaper: “Scientists’ Discovery Cast Doubt on Importance of Genes.” In another example, an article appeared in early 2006 in one of the world’s great newspapers that predicted the probable scientific directions for the coming year. The article included the following commentary: “History also suggests the folly of predicting even gradual developments. Remember gene therapy? Hailed a quarter century ago as the salvation of medicine, it has achieved no real success.” It quoted a noted ethicist at a university famous for its gene therapy studies as saying, “Gene therapy still isn’t a therapy last time I checked.” While I understand their impatience, I hope that these commentators will check again and rethink their concept of “therapy.” Although therapy should certainly require progress toward relief from the suffering of disease or toward an improved quality of life, it does not and should not include a requirement for quick success or absence of failures and reversals. Let me underscore that point with two examples
Figure 2 Past presidents of the ASGT. From the top, left to right: Row 1, George Stamatoyannopoulos, James Wilson, and Savio Woo; Row 2, Inder Verma, Malcolm Brenner, and Joseph Glorioso: Row 3, Donald Kohn, Kathy High, and Mark Kay.
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© The American Society of Gene Therapy
commentary
of now-indispensable modern medical technology that experienced similarly fitful or slow birth and development. Figure 3 shows the pace of development of one of modern clinical medicine’s most important clinical technologies whose evolution is reminiscent of that of gene therapy. An initial period of exuberant application and a rapidly increasing number of human clinical studies were followed by a drastic fall in clinical application as more and more initial studies failed and technical problems mounted. At first glance, this evolutionary history might readily be mistaken for that of gene therapy, but in fact it represents the early phases of bone marrow transplantation, beginning in 1958 and extending into the early 1970s. After the first decade and a half of clinical application for diseases such as aplastic anemia, immunodeficiencies, and hematologic malignancies, the survival rate of patients was still hovering around 1%. It was not until 20 or 30 years later that the tools and methods had improved enough to allow bone marrow transplantation to become an established medical technology and earned E. Donnall Thomas of Seattle the 1990 Nobel Prize in Medicine. A similar story can be told for the therapy of some forms of childhood leukemia. Farber and his colleagues introduced the first anti-neoplastic drug for childhood leukemia in 1948, and even almost 20 years later patient survival was less than 10%. It took another two de-
1578
Figure 3 Human bone marrow transplants from 1958 to 1968 (n = 203). (Adapted from Bortin, M.M. (1970). A compendium of reported human bone marrow transplants. Transplantation 9: 571–587.)
cades for the salvage and even cure rate to reach the levels of 80% or more that are achieved today. Think also about the 30 years or more that have been required to bring the clinical use of monoclonal antibody technology to reality. A period of 30–40 years seems to be a reasonable rule of thumb for delivery of these and some other difficult and conceptually new technologies to effective, wide clinical use. Gene therapy has been in clinical application for only approximately 17 years, on a pace not very different from that of now-established medical technologies. Criticism of the field based on its perceived “slowness” is therefore uninformed and inappropriate. It is impossible to look at the recent history of the field of gene therapy or to listen to the basic and clinical research re-
sults being presented at this meeting and still be patient with the thankfully outdated conventional wisdom about gene therapy. Like so many forms of conventional wisdom, it has turned out not to have been very wise. It should now be evident to even the most skeptical that in a growing number of diseases—childhood immunodeficiencies, several forms of cancer, and others—real patients with real disease have begun to see real clinical benefit from gene therapy. That’s called therapy; it’s not perfect, but it is therapy. Moreover, the pace of clinical studies around the world is increasing. Let us thus now put behind us the thankfully now passé conventional wisdom regarding gene therapy, recognize the forest and not only the trees, and take pride in the progress and achievements of our field. The major tasks now facing the ASGT are not only to foster and present advances in basic and preclinical research but also to work with our colleagues in industry and our partners at the federal level—the NIH through its funding mechanisms, and the Food and Drug Administration and NIH Office of Biotechnology Activities through their oversight functions—to solve the difficult and hugely expensive problem of support for translation to the clinic. To these should be added, of course, the task of bringing a more accurate picture of this important new field of biomedicine to the public.
www.moleculartherapy.org vol. 15 no. 9 september 2007
© The American Society of Gene Therapy
A Decade of Accomplishments: Gene Therapy and the ASGT Theodore Friedmann1 doi:10.1038/sj.mt.6300284
T
his year we celebrate the tenth anniversary of the annual meetings of the American Society of Gene Therapy (ASGT), marking what many feel has been the maturation of the field of gene therapy from promise to incontrovertible therapeutic benefit for people with otherwise intractable disease. One needs only to reflect on where the field was at the time of the first annual meeting a short decade ago to appreciate the great changes that have taken place and the role that ASGT has played in bringing this new form of medicine to clinical reality. A decade ago, the gene therapy community was still coming to grips with the reality that, against all of our rosiest expectations, while we had certainly established a significant body of basic science and animal modeling, we had not yet achieved either convincing demonstration of efficient and stable gene transfer or any evidence of significant therapeutic benefit, to any patient in any of the early clinical studies. We had begun to appreciate that our expectations in those early studies far exceeded our grasp both technically and medically, and that most us had been too optimistic with regard to the apparent simplicity of the concept of gene therapy. Clearly gene therapy needed a new approach to create clinical reality from the conceptual and scientific foundation that had emerged earlier. With some pointed skepticism from some other areas of the scientific and public policy communities and the media, and particularly at the urging of the director of the National InDepartment of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California, USA. Correspondence: Theodore Friedmann, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California 92093, USA. E-mail: [email protected] 1
1576
stitutes of Health (NIH), the gene therapy community was beginning to appreciate the need to develop more rigorous basic and clinical research underpinnings for our field. It occurred to a few of us that a far greater degree of interaction among investigators would help to set appropriate directions for the field. As is often the case, such a task falls on the shoulders of one inspired and inspiring leader. In our case, that person was George Stamatoyannopoulos (Figure 1), who emerged as the principal architect of this new structure; he agitated, urged, cajoled, and browbeat us as only George can do, shaped us into the ASGT, and then quickly became the Society’s first president. No single person has poured as much of his time and effort into the formation and workings of this Society, and the organization’s success is due in no small measure to his service. It is for that reason that the ASGT honored George this year in Seattle—where these meetings began—with a special presidential medal. The growth and development of the Society also owes an enormous debt of gratitude to the long list of Society officers and succeeding presidents: Jim Wilson, Savio Woo, Inder Verma, Malcolm Brenner, Joe Glorioso, Don Kohn, Kathy High, and Mark Kay (Figure 2). Of course, anyone who has ever chaired a committee or served as president of an organization knows that it is the staff that really carries organizations forward and does all the heavy work. The ASGT is no different, and I would like to acknowledge the present Society staff: Ken Jawoski, Mary Dean, Nadine Kikkonen, and Liz Dooley. I want to say a special word about the ASGT’s executive director, Liz Dooley. Liz recently announced that she was having trouble deciding whether she should stay with the Society or go ahead with her
plans to marry a very fortunate man in Boston. Apparently, all our pleading, coaxing, and even dire threats were not powerful enough to force her to stay with us, and we wish her and her new husband happiness and good fortune. One of the major achievements of the Society over the past decade has been the establishment of the journal Molecular Therapy. The journal has become an exceptionally influential and important voice for the field of gene therapy, in large part as a result of the standards of excellence and rigor that were established by the founding editor, Inder Verma—standards that are now so effectively being further developed by the current editorin-chief, David Williams, and the editor, Rob Frederickson. We thank Inder for setting the bar so high and getting the journal off to such a fine start. A year ago ASGT set a number of goals for the following year. These included the initiation of a discussion with the NIH on ways to catalyze progress in gene therapy and other areas of clinical translation; the facilitation of the move of Molecular Therapy to a new publisher, Nature Publishing Group; the fostering of increased interaction and cooperation with other professional societies in gene therapy and related fields; and the strengthening of the Society’s fiscal health in several ways, including the establishment of an endowment. The ASGT leadership identified major areas that were considered obstacles to more rapid progress in clinical applications of gene therapy. These areas included the paucity of funding to cover the huge costs of clinical trials, the difficulty for many investigators of obtaining ready access to clinical-grade gene transfer vectors and other reagents, and the cumbersome funding process for clinical studies. Although we applaud the NIH road map for its emphasis on translational research, we also recognize that clinical applications in gene therapy and other areas of clinical research are struggling with support structures that are not ideally serving the overall clinical research effort in the United States. In the case of vector production and access, some years ago the NIH very wisely created the National Gene Vector Laboratory (NGVL) Program with especially
www.moleculartherapy.org vol. 15 no. 9 september 2007
© The American Society of Gene Therapy
Figure 1 George Stamatoyannopoulos, founding president of the ASGT.
generous support from the National Center for Research Resources, the National Heart, Lung, and Blood Institute, the National Cancer Institute, the National Institute for Diabetes and Digestive and Kidney Diseases, and other NIH institutes. The newly elected vice president of the Society, Ken Cornetta, served as coordinating director of the program, which went on to provide a total of 53 varied clinical-grade vectors used in 37 clinical gene therapy clinical trials involving many hundreds of subjects. In fall 2006 the ASGT proposed to the NIH leadership a dual plan to facilitate and catalyze additional clinical trials. The first recommendation from ASGT was that the NIH continue the valuable NGVL program. To our very great disappointment, the NIH has decided to replace the program with a coordinated vector-production program that will make use of some of the existing NGVL facilities to provide toxicological and preclinical resources and production facilities specifically for lentivirus and adeno-associated viral vector systems. Although this new vector production strategy will certainly facilitate a selected set of clinical trials, it will likely compromise innovation in the development and clinical application of other vector systems. A second recommendation to the NIH was aimed at the development of a more seamless funding structure for supporting clinical trials, and this concept is receiving evaluation by NIH leadership. We strongly urge the NIH leaders to Molecular Therapy vol. 15 no. 9 september 2007
commentary
continue working with ASGT to incorporate this or similar strategies into their translational efforts to facilitate clinical studies in both gene therapy and other areas of clinical research by making the grant-support process for clinical research even more seamless and efficient. Several other goals that we set for the year have had somewhat smoother sailing. The move of the journal to Nature Publishing Group, under the leadership of David Williams and the ASGT publications committee chaired by George Stamatoyannopoulos, has gone well, ensuring that the journal retains its position as the preeminent journal in the field. Similarly, the Society is in discussion with the international gene therapy community to develop more effective international interactions and collaborations. Finally, the ASGT has established an endowment fund and has already received an initial anonymous donation. The Society is now developing plans for fundraising to increase its endowment to ensure its long-term financial health. We certainly welcome your contributions—great and small; personal, academic, and corporate. Finally, a few general comments are in order about the public and scientific image of the field of gene therapy. Science is some-
times portrayed to the public in very confusing and misleading ways, by both scientists and the media. The publication of an early draft of the human genome, including the discovery that there were fewer genes than expected, was greeted by this hilarious headline in a major U.S. West Coast newspaper: “Scientists’ Discovery Cast Doubt on Importance of Genes.” In another example, an article appeared in early 2006 in one of the world’s great newspapers that predicted the probable scientific directions for the coming year. The article included the following commentary: “History also suggests the folly of predicting even gradual developments. Remember gene therapy? Hailed a quarter century ago as the salvation of medicine, it has achieved no real success.” It quoted a noted ethicist at a university famous for its gene therapy studies as saying, “Gene therapy still isn’t a therapy last time I checked.” While I understand their impatience, I hope that these commentators will check again and rethink their concept of “therapy.” Although therapy should certainly require progress toward relief from the suffering of disease or toward an improved quality of life, it does not and should not include a requirement for quick success or absence of failures and reversals. Let me underscore that point with two examples
Figure 2 Past presidents of the ASGT. From the top, left to right: Row 1, George Stamatoyannopoulos, James Wilson, and Savio Woo; Row 2, Inder Verma, Malcolm Brenner, and Joseph Glorioso: Row 3, Donald Kohn, Kathy High, and Mark Kay.
1577
© The American Society of Gene Therapy
commentary
of now-indispensable modern medical technology that experienced similarly fitful or slow birth and development. Figure 3 shows the pace of development of one of modern clinical medicine’s most important clinical technologies whose evolution is reminiscent of that of gene therapy. An initial period of exuberant application and a rapidly increasing number of human clinical studies were followed by a drastic fall in clinical application as more and more initial studies failed and technical problems mounted. At first glance, this evolutionary history might readily be mistaken for that of gene therapy, but in fact it represents the early phases of bone marrow transplantation, beginning in 1958 and extending into the early 1970s. After the first decade and a half of clinical application for diseases such as aplastic anemia, immunodeficiencies, and hematologic malignancies, the survival rate of patients was still hovering around 1%. It was not until 20 or 30 years later that the tools and methods had improved enough to allow bone marrow transplantation to become an established medical technology and earned E. Donnall Thomas of Seattle the 1990 Nobel Prize in Medicine. A similar story can be told for the therapy of some forms of childhood leukemia. Farber and his colleagues introduced the first anti-neoplastic drug for childhood leukemia in 1948, and even almost 20 years later patient survival was less than 10%. It took another two de-
1578
Figure 3 Human bone marrow transplants from 1958 to 1968 (n = 203). (Adapted from Bortin, M.M. (1970). A compendium of reported human bone marrow transplants. Transplantation 9: 571–587.)
cades for the salvage and even cure rate to reach the levels of 80% or more that are achieved today. Think also about the 30 years or more that have been required to bring the clinical use of monoclonal antibody technology to reality. A period of 30–40 years seems to be a reasonable rule of thumb for delivery of these and some other difficult and conceptually new technologies to effective, wide clinical use. Gene therapy has been in clinical application for only approximately 17 years, on a pace not very different from that of now-established medical technologies. Criticism of the field based on its perceived “slowness” is therefore uninformed and inappropriate. It is impossible to look at the recent history of the field of gene therapy or to listen to the basic and clinical research re-
sults being presented at this meeting and still be patient with the thankfully outdated conventional wisdom about gene therapy. Like so many forms of conventional wisdom, it has turned out not to have been very wise. It should now be evident to even the most skeptical that in a growing number of diseases—childhood immunodeficiencies, several forms of cancer, and others—real patients with real disease have begun to see real clinical benefit from gene therapy. That’s called therapy; it’s not perfect, but it is therapy. Moreover, the pace of clinical studies around the world is increasing. Let us thus now put behind us the thankfully now passé conventional wisdom regarding gene therapy, recognize the forest and not only the trees, and take pride in the progress and achievements of our field. The major tasks now facing the ASGT are not only to foster and present advances in basic and preclinical research but also to work with our colleagues in industry and our partners at the federal level—the NIH through its funding mechanisms, and the Food and Drug Administration and NIH Office of Biotechnology Activities through their oversight functions—to solve the difficult and hugely expensive problem of support for translation to the clinic. To these should be added, of course, the task of bringing a more accurate picture of this important new field of biomedicine to the public.
www.moleculartherapy.org vol. 15 no. 9 september 2007