The Growing Clinical Impact of Gene Therapy
Authors: Arthur Nienhuis
Journal: Molecular Therapy (2008)

The privilege of serving as President of the American Society of Gene Therapy affords a unique perspective on the development, evolution, and current status of the field. This perspective is added to that provided by my personal involvement over nearly four decades, initially in molecular biology as the discipline began to develop and now extending to applied gene therapy research. My own judgment is that the field is maturing as a very healthy discipline with a growing potential to improve treatment outcome for a broad spectrum of diseases.Many of us were attracted to the field because of the promised translational potential of applying basic knowledge to disease treatment. As the link between monogenetic disorders and mutations in specific genes became well established, and the genetic code and mechanisms of gene expression were elucidated beginning in the 1960s, the dream of gene therapy emerged. Serious discussion about appropriate disease targets and the ethics of genetic intervention began in the early 1970s. The practical potential for gene therapy was established when reverse transcriptase was discovered and the life cycle of γ-retroviruses became known. In the early 1980s, such viruses were first employed as vectors for transfer of genetic information. The development of packaging cell lines allowed gene transfer vectors to be prepared free of replication-competent retrovirus, paving the way for clinical use. Largely unsuccessful attempts at clinical application of this technology throughout the late 1980s and early 1990s prompted a return to basics with renewed focus on understanding the basic biology of gene transfer—whether by viral or nonviral methods—and the evaluation of gene therapy approaches in appropriate animal models. Clinical success in treating severe combined immunodeficiency came in the first decade of the 21st century. The results of several clinical trials presented at our annual meeting in Boston on 28 May–1 June 2008 expand the promise of the field for treatment of other disorders.Since the Society was founded and began holding annual meetings in 1997, the overall content of each meeting has reflected the status of the field at the time it was held. Throughout the late 1990s and early 2000s, the majority of presentations at the meeting focused on the biology of gene transfer and expression, vector systems, nonviral methods of gene transfer, and evaluation of gene transfer approaches in animal models. In subsequent years, the emergence of RNA interference, oligonucleotide methods, and the potential use of stem cells of various types for therapy further expanded the scope of our annual meetings. In recent years, the immune response to transfer vectors and transgene products has become an increasingly important focus of experimental effort and discussion.This year's annual meeting reflected the growing clinical impact of the field. For example, of the nearly 70 speakers in 18 scientific symposia, 26 speakers (38%) presented results from ongoing clinical trials. Two of the top six abstracts selected for the plenary oral session also reported the results of clinical trials. Cancer, genetic disorders, immunologic disorders such as graft-vs.-host disease, neurodegenerative disorders, and infectious diseases, including AIDS, have all become targets for gene therapy applications. Another aspect of this year's annual meeting was the evidence of growing corporate support for clinical trials and product development. Although not yet realized, there are clearly growing efforts to promote commercial development of gene therapy approaches.During the past year, the President-Elect, David M. Bodine, and I met with several of the National Institutes of Health (NIH) directors and other senior leaders of NIH institutes. Our goal was to educate these individuals regarding the status of gene therapy research and its potential for clinical application. The NIH continues to make a significant investment in basic research related to gene therapy, but the investment in clinical trials is relatively modest. We have had extensive discussions and made recommendations about how funding mechanisms could be developed that provide more integrated support for preclinical development, toxicity studies, vector or nucleic acid production, and conduct of clinical trials. Although sympathetic, the NIH leadership is currently very challenged with difficult financial times. Future leaders of the American Society of Gene Therapy will undoubtedly need to continue the effort to cultivate and develop NIH support.Also needed is ongoing effort to dispel the misperception that gene therapy is inherently risky, when indeed gene therapy interventions have generally been remarkably safe. Although five participants in the gene therapy trials for immunodeficiency have developed leukemia secondary to insertional mutagenesis, two of the patients are in remission following chemotherapy and two other patients are under active treatment. More than 90% of the participants in the several trials have experienced correction of their immunodeficiency and clinical improvement, most without serious toxicity. Our program this year contained much new information about how integrating vectors may be made safer and about systems to evaluate the potential genotoxicity of new therapeutic vectors.One of the challenges that I experienced in my year as President was the severe adverse event that occurred in the trial sponsored by Targeted Genetics. Although much of the press immediately concluded that this event and the unfortunate death of the participant represented yet another failure of gene therapy, no evidence emerged during extensive investigation and discussion by the Recombinant DNA Advisory Committee that implicated the gene therapy intervention in the trial participant's clinical course. Her course was consistent with disseminated fungal infection, diagnosed after death, in the context of systemic immunosuppression. The need for continued vigilance to detect side effects and careful attention to safe trial design remain mandatory, but we should take pride in the overall track record of our field with respect to the safe and ethical conduct of clinical research.I am most grateful for the opportunity to serve the American Society of Gene Therapy in a leadership role. Having completed my responsibilities as President, I look forward to increased personal investment in research efforts to make gene therapy a clinical reality for patients with blood disorders. I am confident that the Society is in good hands with its current and future leaders and that the field will continue to mature in years to come. The privilege of serving as President of the American Society of Gene Therapy affords a unique perspective on the development, evolution, and current status of the field. This perspective is added to that provided by my personal involvement over nearly four decades, initially in molecular biology as the discipline began to develop and now extending to applied gene therapy research. My own judgment is that the field is maturing as a very healthy discipline with a growing potential to improve treatment outcome for a broad spectrum of diseases. Many of us were attracted to the field because of the promised translational potential of applying basic knowledge to disease treatment. As the link between monogenetic disorders and mutations in specific genes became well established, and the genetic code and mechanisms of gene expression were elucidated beginning in the 1960s, the dream of gene therapy emerged. Serious discussion about appropriate disease targets and the ethics of genetic intervention began in the early 1970s. The practical potential for gene therapy was established when reverse transcriptase was discovered and the life cycle of γ-retroviruses became known. In the early 1980s, such viruses were first employed as vectors for transfer of genetic information. The development of packaging cell lines allowed gene transfer vectors to be prepared free of replication-competent retrovirus, paving the way for clinical use. Largely unsuccessful attempts at clinical application of this technology throughout the late 1980s and early 1990s prompted a return to basics with renewed focus on understanding the basic biology of gene transfer—whether by viral or nonviral methods—and the evaluation of gene therapy approaches in appropriate animal models. Clinical success in treating severe combined immunodeficiency came in the first decade of the 21st century. The results of several clinical trials presented at our annual meeting in Boston on 28 May–1 June 2008 expand the promise of the field for treatment of other disorders. Since the Society was founded and began holding annual meetings in 1997, the overall content of each meeting has reflected the status of the field at the time it was held. Throughout the late 1990s and early 2000s, the majority of presentations at the meeting focused on the biology of gene transfer and expression, vector systems, nonviral methods of gene transfer, and evaluation of gene transfer approaches in animal models. In subsequent years, the emergence of RNA interference, oligonucleotide methods, and the potential use of stem cells of various types for therapy further expanded the scope of our annual meetings. In recent years, the immune response to transfer vectors and transgene products has become an increasingly important focus of experimental effort and discussion. This year's annual meeting reflected the growing clinical impact of the field. For example, of the nearly 70 speakers in 18 scientific symposia, 26 speakers (38%) presented results from ongoing clinical trials. Two of the top six abstracts selected for the plenary oral session also reported the results of clinical trials. Cancer, genetic disorders, immunologic disorders such as graft-vs.-host disease, neurodegenerative disorders, and infectious diseases, including AIDS, have all become targets for gene therapy applications. Another aspect of this year's annual meeting was the evidence of growing corporate support for clinical trials and product development. Although not yet realized, there are clearly growing efforts to promote commercial development of gene therapy approaches. During the past year, the President-Elect, David M. Bodine, and I met with several of the National Institutes of Health (NIH) directors and other senior leaders of NIH institutes. Our goal was to educate these individuals regarding the status of gene therapy research and its potential for clinical application. The NIH continues to make a significant investment in basic research related to gene therapy, but the investment in clinical trials is relatively modest. We have had extensive discussions and made recommendations about how funding mechanisms could be developed that provide more integrated support for preclinical development, toxicity studies, vector or nucleic acid production, and conduct of clinical trials. Although sympathetic, the NIH leadership is currently very challenged with difficult financial times. Future leaders of the American Society of Gene Therapy will undoubtedly need to continue the effort to cultivate and develop NIH support. Also needed is ongoing effort to dispel the misperception that gene therapy is inherently risky, when indeed gene therapy interventions have generally been remarkably safe. Although five participants in the gene therapy trials for immunodeficiency have developed leukemia secondary to insertional mutagenesis, two of the patients are in remission following chemotherapy and two other patients are under active treatment. More than 90% of the participants in the several trials have experienced correction of their immunodeficiency and clinical improvement, most without serious toxicity. Our program this year contained much new information about how integrating vectors may be made safer and about systems to evaluate the potential genotoxicity of new therapeutic vectors. One of the challenges that I experienced in my year as President was the severe adverse event that occurred in the trial sponsored by Targeted Genetics. Although much of the press immediately concluded that this event and the unfortunate death of the participant represented yet another failure of gene therapy, no evidence emerged during extensive investigation and discussion by the Recombinant DNA Advisory Committee that implicated the gene therapy intervention in the trial participant's clinical course. Her course was consistent with disseminated fungal infection, diagnosed after death, in the context of systemic immunosuppression. The need for continued vigilance to detect side effects and careful attention to safe trial design remain mandatory, but we should take pride in the overall track record of our field with respect to the safe and ethical conduct of clinical research. I am most grateful for the opportunity to serve the American Society of Gene Therapy in a leadership role. Having completed my responsibilities as President, I look forward to increased personal investment in research efforts to make gene therapy a clinical reality for patients with blood disorders. I am confident that the Society is in good hands with its current and future leaders and that the field will continue to mature in years to come.