The objective of this Program Project is to develop gene-based therapies for hemophilias A and B. The program project consists of four projects and two cores that address the overall goal through basic, translational, and clinical studies. In Project #1, D. Katherine High will carry out a series of studies designed to characterize the molecular basis of long-term expression of AAV transduced muscle cells, to determine whether muscle cells can properly post-translationally modify factor IX, and to assess whether specific modifications to the factor IX expression cassette in the vector can lead to higher levels of transgene expression. In Project #2, Dr. Haig Kazazian will use both retroviral and adenoviral vectors directed into skin and liver to correct factor VIII deficiency in murine and canine models of hemophilia A. Preliminary data show that high levels of recombinant factor VIII can be expressed from the skin. This project will also conduct studies on a novel vector based on retro-transposons. In Project #3, Dr. Mortimer Poncz will explore a novel approach to gene therapy for the hemophilias by introducing into hematopoietic cells a vector with a megakaryocyte-specific promoter. Dr. Poncz' studies will determine whether factor VIII expressed in this manner can effectively treat hemophilia A. In Project #4, Dr. Alan Cohen will evaluate the hypothesis that AAV-mediated, muscle-directed gene therapy can ameliorate the clinical phenotype in humans with hemophilia B without untoward side-effects. In addition to these projects, the Program Project will include two cores, an Administrative Core directed by Dr. High and Coagulation Core directed by Dr. Sriram Krishnaswamy, which will provide expertise in measurement of clotting factor antigen and activity levels in mice, dogs and humans. Methods available of factor Ix and factor VIII. Interactions among the projects and cores are extensive. Project #1 will develop pre-clinical data that will be direct utility to the studies ongoing in Project #4. In turn, results from Project #4 will provide new directions for the effectors in Project #1. Projects #1 and 2 are collaborating for development of a novel vector and on extension of a successful epidermal-based approach to factor IX. Projects #2 and #3 will benefit greatly from interactions with Project #1 utilizing the considerable experience of Dr. High's group in small and large animal models of hemophilia, and with viral vector-mediated gene transfer. Projects #2 and 3 have strong ongoing collaborations centered on the use of the factor VIII knockout mice and various human and mouse factor VIII cDNAs. Once vectors have been demonstrated to be efficacious in animal models,, translation to clinical investigation will be facilitated by experience gained and resources available in Project #4. All four projects will make use of the Administrative and the Coagulation Core.
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