This is a competitive renewal application for a Program Project Grant entitled Gene Therapy for Hemophilia. The PPG consists of 4 projects and 3 cores. Three of the projects are continued from the previous PPG and one is new. Project 1, directed by Dr. Valder Arruda, analyzes the efficacy of two novel methods for delivering large doses of vector to skeletal muscle. Both methods rely on intravascular delivery of vector, and have resulted in transduction of extensive areas of skeletal muscle in large animals after a single intravascular injection. Project 1 will examine dose-response, the efficacy of alternate serotypes, and the possibility of re-administration of vector, for both approaches. Project 1 will also examine the role of variant F.IX molecules with better egress from skeletal muscle or higher specific activity. Project 2, directed by Dr. Katherine High, examines critical safety issues that must be addressed before the intravascular delivery approach can be translated to clinical use. She will explore the immune response to the transgene product, and the risk of germline transmission of vector DNA, in both approaches. She will also determine the maximal levels of fully functional F.IX that can be synthesized in a given mass of skeletal muscle. Project 3, directed by Dr. Haig Kazazian, will explore AAV-mediated, liver-directed gene transfer approaches for hemophilia A, with an emphasis on analysis of novel AAV serotypes, in mice and dogs with hemophilia A. Project 4, directed by Dr. Mortimer Poncz, will continue his highly successful work of the previous funding period, in which he demonstrated that expression of F.VIII in megakaryocytes (and thus in circulating platelets) could correct the bleeding diathesis of hemophilia A mice. In particular he will explore the kinetics of clot formation in the presence of F.VIII-expressing platelets, and will define the cell biology of F.VIII storage and secretion from the gene-modified platelet. He will also examine variant F.VIII molecules with increased specific activity, and will develop lentiviral vectors to allow pursuit of this strategy in megakaryocytes of large animals. These projects will be supported by three cores. Core A, the Administrative Core, will support and co-ordinate scientific interactions among the group. Core B, the Vector Core, will provide research grade AAV and lentiviral vectors for the investigators. Finally, Core C, the Large Animal Models Core at UNC-Chapel Hill, will provide access to hemophilic dogs and will provide expertise in coagulation testing in these animals.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-PPG-R (F1))
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Link, Rebecca P
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Children's Hospital of Philadelphia
United States
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