The Ninth Annual Meeting of the American Society of Gene Therapy
Authors: Robert M. Frederickson
Journal: Molecular Therapy (2006)

The 9th annual meeting of the ASGT took place in Baltimore, MD from the 31st of May thru the 4th of June. Over 1100 abstracts were submitted and attendance reached over 2000. In addition, more than 50 companies and institutions showcased products and services representing the latest advances in oligonucleotide, gene and cell therapy research. The development of RNAi and microRNAs as genetic tools and as therapeutics continued to be a focus of intense study. New results provided further support for the proven promise of gene therapy to cure inherited immunodeficiencies and to treat diverse tumors. In addition, various studies examined further the issues of safety and genotoxicology of early-generation retroviral vectors or explored newer vector designs that aim to obviate such issues. This year's meeting for the first time included an International Symposium that reported on advances in basic and clinical work in gene transfer research around the globe, and a Manufacturing Symposium to discuss some of the technological barriers and solutions to allow for improved clinical grade vectors and cells needed for human trials. In addition, a special NIH-NIDDK sponsored satellite session was held this year to examine the issue of vector-induced tumors, as was a session that addressed the potential of gene transfer to alter complex behaviors, and the ethical issues raised by such approaches. Indeed, the society continues to be proactive in dealing with public education and the ethics of gene transfer research, and in another first, the society sponsored a congressional briefing on gene transfer research on Capitol Hill and a science writer's session for selected media. The exploitation of RNAi by expression of short hairpin (sh)RNA holds promise for functional genomics and human gene therapy. Dirk Grimm described recent results demonstrating fatality in mice that may reflect oversaturation of cellular pathways that mediate the metabolism of micro/shRNAs. The work suggests that shRNAs will need to be optimized for both dose and sequence, and that strong control over intracellular shRNA expression will be mandatory to avoid the risks inherent to application in vivo of the technology. Brian Brown of the Naldini lab presented an ingenious approach to target gene transfer and expression to specific cell lineages. The authors engineered a lentiviral vector to contain sequences with perfect complementarity to an endogenous hematopoietic-specific miRNA so as to restrict transgene expression to non-hematopoietic lineages. Importantly, the use of such a vector prevented vector clearance by the immune system. Gene therapy has been previously shown to treat infants with X-linked severe combined immunodeficiency (X-SCID). New results presented at the meeting showed that gene therapy could benefit older patients as well. Gene-corrected cells were introduced into three patients, aged 10, 11 and 14 years of age. Although the level of gene corrected cells in their blood varied post-transplant, all three patients have shown improvement in their condition and reduced symptoms. The first gene transfer to bone marrow with foamy viruses was reported to correct leukocyte adhesion deficiency in dogs, by workers from the lab of Thomas Bauer and Dennis Hickstein. The results demonstrated the safely and effectiveness of foamy viruses for delivering genes into bone marrow stem cells to correct genetic disease. Much interest accompanied the report of gene transfer to treat chronic granulomatous disease (CGD). Manuel Grez described the treatment of two adult CGD patients by inserting the missing gene (gp91phox) into the patients' bone marrow cells. Both patients showed response to the treatment, which was enhanced by an increase in the number of gene corrected cells due to activation of MDS1/EVI1 and PRDM16 after retroviral integration. No hematological abnormalities were detected in the patients, although longer-term follow-up will be necessary to assess the safety of the approach. Grez reported that one of the patients developed severe sepsis and died 27 months after transplantation with gene-modified cells. Gene marking was still high at the time of death (50-60%), and the gene marked hematopoiesis was still oligoclonal. However, superoxide production by the gene transduced cells had decreased with time and at the time of death only 5-10% of the patient's neutrophils were functionally active. Grez has speculated that epigenetic modifications of the proviral genome may have led to transcriptional silencing of the vector. A highlight of the meeting each year is the George Stamatoyannopoulos Lecture, which was given this year by C. David Allis. Allis discussed the role of the “histone code” in the regulation of gene expression. Chromatin modification and the enzymes that mediate these modifications are an important means of regulation of gene expression. Understanding the rules governing this regulation is key for those working in gene transfer research, because the expression of integrated genes is subject to the influence of surrounding chromatin, a phenomenon known as chromosomal position effects, which can lead to silencing or inappropriate expression of the transferred therapeutic gene. Allis was followed by Celia Witten who outlined the FDA's outreach efforts to the gene therapy community. In his presidential address, outgoing president Mark Kay highlighted the many activities of the society over the past year. In addition to noting the various new sessions added to the meeting agenda, Kay discussed ongoing efforts of the ASGT to develop further relationships with gene therapy societies worldwide. Kay also noted the continuing success of the society's flagship journal, Molecular Therapy, and summarized the results of the year-long process during his tenure to evaluate and select a new publisher for the journal. Beginning in January 2007, Nature Publishing Group will take over publication of the journal, which will launch with a new look online and in print. Kay cautioned that the journal will no longer be available on Elsevier's ScienceDirect platform and urged members to contact their local institutional librarians to ensure continued access to the journal. Of course, ASGT members will continue to benefit from print and online access to the journal. Kay also addressed issues related to the coverage of the gene therapy field in the lay press. This coverage has appeared to continue to focus on negative results in clinical trials and the perceived slow pace of progress. Much of the blame for this coverage is thought to derive from early hype surrounding this relatively young field. Kay reminded the audience that monoclonal antibody therapies and bone marrow transplantation, today both remarkably successful clinical approaches, took decades to be validated. In an effort to improve coverage and understanding of gene transfer as a therapeutic modality, the society launched in late 2005 a Public Outreach and Education committee, chaired by former ASGT President Savio Woo. An important ongoing project of the committee is to revamp the ASGT website to include scientific and clinical trial explanations at a level geared towards a high school student. Funds were raised from a number of academic institutions that allowed the society to hire a public relations firm to help the society meet its public education goals. Kay noted that the current US administration was not friendly to biomedical research and he urged members to write their representatives to voice their concerns. Finally, Kay highlighted some of the field's successes over the past year, such as the licensing of two gene therapy products in China for the treatment of cancer and the continued demonstration of efficacy following corrective gene transfer to adenosine deaminase (ADA)- and X-SCID patients in Europe. Moreover, Kay noted that trials are underway that employ RNAi-based therapeutics for age-related macular degeneration and respiratory syncytial viral infections. Kay ended by stressing the need for the society to continue to evolve, and to reach out to those working with oligonucleotides and stem cells, as examples of two communities with which the gene transfer community has much overlap. An important aspect of vector development is the understanding of the mechanisms involved in vector entry and post entry processing prior to final molecular events resulting in successful transduction. Following his address, Kay introduced this year's Presidential Lecturer, Dr. Joseph Sodroski, who discussed his work on the role of TRIM5a in blocking retroviral infection in primates. This years Outstanding New Investigator Awards went to Alberto Auricchio, Dongsheng Duan, Salima Hacein-Bey Abina, and Punam Malik. Auricchio discussed work from his lab aimed at exploiting AAV serotypes for human gene therapy. Auricchio's work has focused largely on models of recessive and dominant retinal disease. Duan also discussed exploitation of the AAV vector and ways of increasing its limited genetic payload. Duan's approach involves delivering two vectors simultaneously carrying two halves of a larger transgene. Reconstitution of the full-length transgene is then achieved by recombination mediated by the AAV inverted terminal repeat region by head to tail splicing. Duan's ultimate aim is to exploit the system to treat muscular dystrophy. Dr. Hacein Bay-Abina presented follow-up data on patients treated in the French trial for X-SCID, including a large-scale analysis of patterns of retroviral integration in the patients' gene-corrected cells. Malik discussed data from her group making use of lentiviral vectors for erythroid lineage-specific gene expression, position effects and silencing following transduction of hematopoietic stem cells for gene therapy of red blood cell diseases. As mentioned above, this year's meeting included a session devoted to late-breaking abstracts. The first of these was presented by Thomas Bauer on the use of foamy virus vectors to treat canine leukocyte adhesion deficiency as noted above. The second was presented by Luk Vandenberghe, who described a structural domain of the AAV capsid that determines its presentation for T-cell activation. Activation of T cells has been implicated in liver toxicity in a recent trial of gene therapy for hemophilia B. Francesca Storici presented data examining DNA repair and gene targeting to a chromosomal double-strand break with DNA and RNA oligonucleotides. Finally, Larry Chan discussed the use of a helper-dependent adenoviral vector to deliver Ngn3 to induce pancreatic islet neogenesis in the livers of diabetic mice. Chan showed that they were able to reprogram albumin-expressing liver cells into mature islets that completely reversed the diabetic phenotype. A special satellite symposium chaired by Jim Wilson provided a forum to evaluate the current data and thinking on the ability of gene vectors to induce or enhance tumor development. The past few years has seen a tremendous effort to understand the mechanisms of lentiviral/retroviral integration and the role in development of tumors. Luigi Naldini presented cutting-edge work that directly measured rates of tumor formation in lentiviral-vector treated animals and also studied integration events. The relationship between AAV gene transfer and tumor formation remains far less clear, although current data appear to rule out integration as a causative agent. It has been suggested that tumor formation by these vectors may be linked to the transgene product and pre-existing inflammation of the liver, although clearly much more needs to be done in this area. A confounding issue is the inherent susceptibility of some animal models of disease to develop tumors, and the need for the study of sufficient numbers of animals to derive meaningful conclusions. The comments here are only cover a small aspect of the many excellent presentations and posters at this year's meeting. However, interested readers can find a more complete review of the work presented at this year's meeting on the ASGT website (www.asgt.org). Next year's meeting will celebrate the 10th anniversary of the founding of the society, and will be held for the third time in Seattle. A number of special events are planned to celebrate the anniversary and the indication that gene therapy is beginning to play an important role in the treatment of disease. The George Stamatoyannopoulos Lecture will be presented by Dr. Judah Folkman. Folkman will review the evolution of cancer therapy that involves interference with the vascular supply to tumors. The evolution of this approach has been long and complex, but is beginning to show important therapeutic results. The meeting will also include a Presidential Lecture by Cynthia Kenyon. Kenyon has pioneered the study of C. elegans as a model for the understanding of the genetic mechanisms underlying aging and has identified genes that affect the longevity and activities of C. elegans. This model represents one of the most important extensions of a traditional view of genetic correction for human disease. The society will also host a special symposium that will review the progress in understanding and treating both “simple” monogenic diseases such the inborn errors of metabolism as well as complex diseases such as cancer and AIDS. The symposium is intended to mark the maturation of the field of gene therapy from concept to clinical reality. The symposium will be opened by Prof. Sir David Weatherall, who will review how the complex pathogenesis of monogenic disease can complicate implementation of therapy. Dr. Maria Grazia-Roncarolo will next review the strikingly effective gene therapy treatment, possibly even the “cure”, of several monogenic childhood severe combined immunodeficiency diseases. Dr. Malcolm Brenner will then describe advances in gene therapy approaches to much more complex multigenic diseases, as exemplified by a number of cancers. Finally, Nobel Prize winner Dr. David Baltimore will present new concepts of gene therapy approaches for genetically complex diseases such as cancer and AIDS. The symposium will be followed by a reception and an opportunity for the participants to meet with the speakers. An additional special symposium is being planned by Dexi Liu and colleages to celebrate the 20th anniversary of the discovery of DOTMA, the first synthetic vector for gene delivery, and the 25th anniversary of the use of electroporation for mammalian cell gene transfer. See you in Seattle!