Main Text
The early 1990s was an exciting time to enter gene therapy, with initiation of the first set of clinical trials, the founding of the first biotechnology startup in the field, and optimism based on encouraging results in rodent models and some types of human cell studied in vitro. I personally jumped right from my postdoc in Art Nienhuis’s lab to running several of the first gene marking clinical trials as a newly-minted tenure-track faculty member. However, by 1995, most of us were beginning to realize it would not be quite so easy, despite the elegance of the concepts and our enthusiasm. The early trials showed little persistence of genetically corrected cells and no credible evidence for clinical improvement. Harold Varmus, then director of the NIH, commissioned a blue-ribbon panel chaired by Stewart Orkin and Arno Motulsky with the aim of examining the current status of gene therapy and providing recommendations for future NIH support in the area. The conclusions of the report, issued in December 1995, were quite sobering, focusing on the lack of clinical efficacy, the overselling of results from both laboratory and clinical studies, and the negative impact of a lack of sufficient understanding of both disease pathophysiology and the basic science of gene transfer vectors. The report conclusions specifically called for more research into these basic questions, leading to well-designed exploratory clinical trials, along with improved training in the necessary research areas, and better and more honest communication between scientists and the public.
In the context of this report and the even more challenging bars it set for future research, 1996 was perhaps a surprising time to be founding a society focused on gene therapies. I vividly remember sitting around a table in the corner of a bar in Taos, New Mexico in early 1996, a few weeks after the report was issued, with other speakers from a Keystone Symposium entitled “Gene Therapy with Hematopoietic Stem Cells in Genetic Diseases and Cancer.” George Stamatoyannopoulus, my mentor (Art Nienhuis), my colleagues at the NIH (David Bodine and Michael Blaese), Don Kohn, and Scott McIvor were some of the notables I recall being present as we drew up plans for the founding of the American Society for Gene Therapy (ASGCT). We felt the need to begin to professionalize our endeavors, bringing together the quite diverse investigators who had been working on many different targets for gene therapies all struggling with the same issues, i.e., poor efficiency of gene delivery into target cells and limited or dysregulated expression of the transgenes. We hoped ASGT would serve as a place to share information; engage the public, funders, and regulators; and stimulate students and postdoctoral fellows to further pursue their interest in the field. By this time, both the Europeans and the Japanese had already formed societies and held their first annual meetings.
ASGT got off to an excellent start, facilitated by the incredible dedication of its founding President, George Stamatoyannopoulus, who almost single-handedly organized and hosted the first annual meeting held in Seattle in 1998. Scientific findings and technical advances were coming fast and furious in the late 1990s, with the first demonstration of an efficient replication-competent lentiviral vector by Naldini and coworkers, long-term mitigation of hemophilia B first in murine and then in canine models via adeno-associated virus (AAV)-mediated gene transfer, use of non-human primate and immunodeficient murine-human xenograft models to improve transduction of human hematopoietic stem cells, and the discovery of RNA interference, among many others. However, the 1999 death of 19-year old Jesse Gelsinger, resulting from administration of an adenoviral vector, brought home to everyone in the field the limits of understanding and the need to move forward carefully, relying on more predictive large animal models and more rational clinical trial design.
Membership in ASGT and attendance at the meetings grew rapidly in the first 5 years. The founding of Molecular Therapy in 2000 was the next major step in ASGCT’s development. Under the leadership of founding Editor-in-Chief Inder Verma and his successors, along with managing editor, Rob Frederickson, the journal rapidly became high impact and successful, providing another venue for communicating progress and providing information.
ASGT’s “midlife” during the first decade of the new century was marked by ups and downs in NIH funding, public interest, trust in the field, and clinical progress. The first unequivocal clinical mitigation of serious human diseases via gene therapy was finally achieved in severe combined immunodeficiencies, unfortunately followed soon thereafter by the occurrence of genotoxic leukemias resulting from activation of adjacent proto-oncogenes via strong enhancers present in standard murine retrovirus vectors. Promising early human clinical trials in hemophilia B were hampered by immune responses to the AAV vector. The response to these hurdles was a rapid explosion of knowledge regarding vector integration patterns and vector immunogenicity, ultimately leading to the design and rapid implementation of safer and more effective vectors, all communicated and accelerated by the interactions between investigators at the ASGCT meetings. The society changed its name to the American Society for Gene and Cell Therapy in 2007 to mark the synergism between progress in the development of both cell and gene therapies, the frequent combination of both approaches in single treatment products, and the common regulatory and manufacturing challenges faced by both fields.
This brings us to the past 5 years, a period that shows every sign of being the beginning of an age where gene therapies do truly become a therapeutic reality for patients with both rare and common diseases. Multiple genetic disorders, including several additional immunodeficiencies, two neurologic metabolic disorders, hemoglobinopathies, hemophilia, and a form of inherited blindness, have now been successfully treated with viral vector-based gene therapies. Oligonucleotide and RNA therapeutics have shown great promise for forms of muscular dystrophy. And the antitumor efficacy of chimeric antigen receptor T cells engineered against refractory hematologic malignancies has surpassed expectations again and again. The investment community and big pharma have taken note, supporting and partnering with multiple new startups in the areas of gene and cell therapies. Attendance at the ASGCT meetings has risen again, including, for the first time, a substantial number of attendees from industry. Exhibitor booths have proliferated, and the hallways at the last few ASGCT meeting have pulsed with more excitement and activity than ever before. Several gene therapy products have been approved in Europe, and approval of at least one product in the US seems imminent.
To mark this progress and to celebrate the 20th annual meeting, George Stamatoyannopoulus recruited a group of leaders who have contributed to these landmark clinical trials to author a series of review articles highlighting these advances in this issue of Molecular Therapy. It was impossible to encompass every advance or every subfield falling under the ASGCT and Molecular Therapy umbrella, but we hope this set of articles will set the benchmark for where we are now and set the stage for an even brighter future, serving as an inspiration for new investigators entering our field.