This is the second competitive renewal application for a Program Project Grant (PPG) entitled Gene Therapy for Hemophilia. The PPG consists of 3 projects and 3 cores. All three projects are continued from the previous PPG. Project 1, directed by Dr. Valder Arruda, will take advantage of a novel Factor (F.) IX variant (F.IX Padua, R338L) that has 10-fold the activity of wild type F.IX. Dr. Arruda will study F.IX Padua's efficacy and potential side-effects in the canine hemophilia 8 models as well as study the molecular basis for F.IX Padua's increased specific activity. Project 2, directed by Dr. Katherine High, will examine the safety and efficacy of continuous expression of Factor VIla after intravascular delivery to skeletal muscle of an AAVFVIIa vector in hemophilic dogs;she will also develop an inducible Vila vector that can be regulated by doxycycline. Project 3, directed by Dr. l /lortimer Poncz, will continue his successful work of the previous funding period to understand the details of thrombus development by platelet-delivered F.VIII and to develop strategies to avoid observed clot instability while retaining platelet F.VIII activity in the presence of inhibitors in both hemophilia A mice and dogs. These 3 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 and in vivo clotting models in these animals. This PPG presents three highly innovative projects to advance the care of patients with inherited bleeding disorders, including hemophilia A, hemophilia B, and patients with inhibitors to F.VIII or F.IX. The three projects investigate therapeutic strategies that utilize skeletal muscle or hematopoietic cells as targets for gene transfer, and thus are feasible for clinical translation even for those with liver disease due to viral hepatitis, which includes a large fraction of adults with severe hemophilia. The projects are highly interactive, and all three take full advantage of the proposed cores.

Public Health Relevance

Hemophilia A and B account for most of the inherited bleeding disorders in the United States of America, affecting 1 in every 5,000 males. Present treatments replacing the missing coagulation factors are effective, but with significant limitations. This Program Project will pursue animal studies of a number of complementary, innovative gene therapy approaches for the treatment of these bleeding disorders that may provide better care and that may also serve as new approaches for the care of other inherited disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
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Children's Hospital of Philadelphia
United States
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George, Lindsey A; Sullivan, Spencer K; Giermasz, Adam et al. (2017) Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med 377:2215-2227
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