? ? The following application is to continue support an inter-institutional Program of Excellence in Gene Therapy (PEGT). The participating institutions include: Stanford University, The Children's Hospital of Philadelphia, and The University of Pennsylvania and investigators with a well-documented history of collaboration including the successful implementation of an AAV- liver based gene therapy trial. We have used the information learned from this trial to develop new preclinical clinical trials. In this application, there are 3 preclinical gene therapy proposals 2 clinical trials. There are three """"""""local"""""""" core proposals (for the investigators of this PEGT), a Research Grade AAV, Administrative, and Clinical Core. We also propose a unique training program to offer post-doctoral candidates research training in gene therapy. A National Morphology core is designed to provide all NHLBI investigators with unique services to further advance the study of gene transfer and/or transgene expression in animal models. The common theme of this proposal is AAV-mediated gene based therapies for hemophilia: (#1) ? Dr. Katherine High will test the hypothesis that the bleeding diathesis in hemophilia patients with inhibitory antibodies can be treated with a gene therapy approach. This grant builds on a decade of clinical experience with recombinant Vila and on the investigator's expertise with coagulation proteins and their expression using AAV vectors. (#2) Dr. Haig Kazazian and colleagues will build on their success in treating hemophilia A mice using new AAV serotypes. They will determine optimal conditions for liver-based gene transfer in fetal monkeys, and validate these conditions in neonatal monkeys and neonatal hemophilia A dogs. (#3) Dr. Mark Kay plans to develop novel AAV pseudotyped vectors that may evade immunological parameters that have limited efficacy in human trials. His group will use non-mammalian primate AAVs and snuffled capsid libraries to make novel vectors and test them in the appropriate animal models. (#4) Dr. Catherine Manno will continue an AAV-2 liver ? based trial using transient immunosuppressive therapy to attempt to eliminate a T cell mediated elimination of transduced hepatocytes in humans. (#5) Dr. Bertil Glader is proposing a clinical trial using AAV-8 vectors that based on preclinical studies suggesting that this vector pseudotype has advantages over AAV-2. Nonetheless, as has been learned during the previous funding period, even the best animal models and preclinical studies cannot always predict the outcome in humans, supporting the need for multiple approaches. The combined efforts of this group of investigators have a long and productive history that will further research towards a cure for hemophilia. (End of Abstract) ? ?
