The Sixth Annual Meeting of the American Society of Gene Therapy
Authors: Robert M. Frederickson
Journal: Molecular Therapy (2003)

Each year, the annual meeting of the American Society of Gene Therapy (ASGT) provides an opportunity to look back and reflect upon the “year in gene therapy” that was, and the occasion of the sixth annual meeting provided much to ponder. The major story over the past year has of course been the serious adverse events that occurred in the French trial for gene therapy for XSCID and the continuing study of the biology that underlies these events. As ASGT president, Don Kohn, notes in this month's editorial how- ever, we must keep such setbacks in perspective, and not lose sight of the forest for the trees. Setbacks occur as frequently as advances in the sciences, and often end up teaching us something we did not previously know. And happily in this case, both patients who developed the lymphoproliferative disorder due to the gene transfer have now responded well to treatment. Much attention is now being given to the nature of the genetic neighborhoods into which retroviruses and other integrating vectors land. Evidence is accumulating that the location of insertion is not as random as had once been thought. Moreover, the tendency of vectors to land in actively-transcribed chromatin can have a dramatic effect on transgene expression, and the vector and transgenes them- selves can strongly impact their new genetic neighbors. This year's George Stamatoyannopoulos Lecturer was Gary Felsenfeld, who presented work from his lab and the work of other researchers studying and mapping the genetic ele- ments that control position effect variegation of gene expression and silencing. Genes are often sufficiently close together in the genome that powerful enhancers, capable of functioning at considerable distances from promoters, might be able to activate adjacent genes inappropriately. Dr. Felsenfeld described the properties of insulators, a diverse group of sequence elements that either prevent the encroachment of condensed chromatin into active regions, or that block the action of an enhancer on a promoter when placed between them. Further study and understanding of these elements seem bound to be useful in gene transfer technology to insulate integrated transgenes from less desir- able genetic neighbors, and to inhibit the inappropriate acti- vation of genes by viral vector control elements, as appears to have happened in the French study. An interesting surprise from the development of the pro- liferative disorder in the French study was that it appeared to arise from a single genetic “hit.” Oncogenesis has been thought to be a multistep process of sequential genetic lesions that take a cell from a normal phenotype through various stages of hyperplasia to a blatantly malignant phe- notype—at least for solid tumor development. The develop- ment of leukemia may not necessarily follow such a path, and the adverse event in the French trial may eventually provide valuable information on the mechanism of leuke- mogenesis. Robert Weinberg presented this year's Presidential Symposium, outlining work in his lab and oth- ers to understand the diversity and idiosyncratic nature of the genetic roadmap leading to cancer development in spe- cific tissues, as well as the effects of surrounding tissues on the cancer cell. The Corporate Symposium this year focused on oncolyt- ic viruses for cancer therapy, many of which have made their way to the clinic. While promising results have been obtained in many cases, a familiar theme was the need for better systems to evaluate these antitumor agents and the need to develop viruses that are more robust in their effects upon tumor cells relative to other cells of the host. Nevertheless, the symposium highlighted the slow but inex- orable march of gene therapeutics out of the lab and into the complex world of clinical medicine. It would be impossible here to give more than a bird's eye view of the work presented at this year's meeting. With over 1200 abstracts submitted from laboratories around the world, the meeting represented the breadth of research into molecular and cellular therapies based on gene transfer and gene modification technology. Some may eventually work in patients, and many will not. However, as outgoing ASGT President Joe Glorioso stated in his farewell address to the attendees, “On balance, we are pioneering a new wave of genetic medicines. Progress is not without setbacks, and the path requires faith, innovation, stamina, and reason." Correction: Last Month's Meeting Report on the 3rd Cabo Gene Therapy Focus Panel inadvertently omitted this list of panel participants: Estuardo Aguilar-Cordova, Advantagene Laura Aguilar, Harvard Medical School Flavia Borelli, Cell Genesys Larry Couture, City of Hope Ronald Crystal, Cornell University Robert Frederickson, Molecular Therapy Darrell Galloway, Naval Medical Research Center Peter Jahrling, US Army Doug Jolly, Biomedica David Kaslow, Vical Saleen Khan, University of Pittsburg David Kirn, Cell Genesys Scott McIvor, University of Minnesota Bernie Moss, NIH John Nemunitis, US Oncology David Olson, Genteric CJ. Peters, University of Texas Michelle Rives, Baylor College of Medicine Dan Solomon, Scripps Steve Scherer, Baylor College of Medicine Leonard Smith, US Army Jeffrey Ulmer, Chiron Inder Verma, Salk Institute Jim Wilson, University of Pennsylvania Savio Woo, Mount Sinai School of Medicine Margaret Liu, Transgene SA