Gene Therapy for Hemophilia and Heart Disease Overview 
    - Mark A. Kay, MD, Principal Investigator

The inter-institutional Program of Excellence in Gene Therapy (PEGT) includes Stanford University, The Children's Hospital of Philadelphia, and University of Pennsylvania. The investigators have a well-documented history of collaboration. The overall goal is to develop the scientific principles to advance basic, preclinical and clinical gene therapy. In this program, there are 3 basic/preclinical gene therapy projects, and 3 clinical trials within two clinical projects. In addition we offer an individualized training program in clinical gene therapy. The goal of which is to graduate rigorous and outstanding post doctoral fellows into independent investigators who will continue to advance the field of gene therapy. The proposals within the PEGT have a common theme; gene based therapies for hemophilia based on recombinant adeno-associated viruses as a vector for preclinical and clinical gene transfer. A brief summary of each project follows: 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 VIIa and on the investigator's expertise with coagulation proteins and their expression using AAV vectors. Dr. Haig Kazazian and colleagues will work in collaboration with Drs. High and Kay to develop optimal liver -based rAAV vectors for factor VIII deficiency, and then test those vectors in appropriate pre-clinical animal models. Dr. Mark Kay plans to develop a non-surgical asanguinous liver perfusion technology in large animals for tissue specific delivery of vectors as a prelude to clinical application, and to address important biological questions related to AAV transduction of liver. His group will also use this approach for preclinical evaluation of a new integrating, non-viral vector. Dr. Bert Glader proposes two liver-based AAV trials for hemophilias A and B. Dr. Catherine Manno has developed a new AAV muscle-based clinical trial for factor IX deficiency based on proposed preclinical studies to select an improved expression cassette, vector serotype, and site of vector injection. There are two supporting cores (for the investigators of this PEGT), a Research Grade AAV and Clinical Core. There is a National Morphology Core open to NHLBI Investigators. This core facility allows for tissue analyses and vector characterization related to gene transfer studies. In total, this highly interactive group of scientific and clinical investigations will be used to enhance progress in clinical gene therapy.

- Project 1 - Gene Based Approach to Treating Hemophilic Inhibitors. K. High

- Project 2 - Modeling Gene Therapy of Hemophilia A via Liver Directed Gene Expression. H. Kazazian

- Project 3 -Isolated Liver Perfusion for rAAV and Non-Viral Vector Delivery. M. A. Kay

- Project 4 - A Phase I Safety Study in Patients with Severe Hemophilias A and B Using AAV Vector to Deliver the Gene for Human Factors VIII and IX into the Liver. B. Glader

- Project 5 - A Novel Vector for Gene Transfer for Hemophilia B. C. Manno

- National Service Core: