The Francis Owen Blood Research Laboratory (FOBRL) will be the location of the Animal Core in this Program Project Grant (PPG) for Gene Therapy of Hemophilia. Our main objective is to use dogs with hemophilia A and hemophilia B to determine the most efficient and least toxic method of gene therapy for these inherited disorders and to monitor the expression and persistence of F.VIII and F.IX. We hypothesize that replacement of F.VIII and F.IX by gene therapy will correct the bleeder phenotype in hemophilia A and B dogs, respectively. The FOBRL, established in 1960 and dedicated to the preservation and study of severely affected animal models of bleeding disorders, has been a resource for the study of canine hemophilia A and B. Both canine hemophilia A and B in the FOBRL colony are inherited as a sex-linked recessive traits; hemophilia A is due to an intron 22 inversion and hemophilia B is due to a point mutation in the catalytic domain of F.IX. Affected dogs have no detectable antihemophilic factor functionally or antigenically. Infusion of canine or human F.VIII and F.IX concentrates corrects prolonged partial thromboplastin times and halts the severe bleeding episodes characteristic of the hemophilias. Correction of canine hemophilia A and B by liver transplantation presaged successful vector-mediated gene therapy. This strain of hemophilia B dogs is the first animal model of hemophilia to enjoy long-term benefit of gene therapy with continuous expression of canine F.IX mediated by AAV-vectors from the High laboratory for over 7 years without production of anti-canine F.IX antibodies. Some dogs have exhibited a lower bleeding rate supporting our hypothesis. Current limitations of hemophilia gene therapy include low levels of transgene expression and the relative paucity of strategies for hemophilia patients with inhibitory antibodies. The Core function, then, is to provide professional and technical personnel and laboratory facilities for the conduct of F.VIII and F.IX gene transfer and vector toxicity studies for this PPG to address these limitations through novel strategies proposed in each of the four projects. Production of the hemophilic dogs dedicated to this PPG is supported by HL63098 """"""""Maintenance of Animal Models of Hemophilia and VWD."""""""" This core will support experimental dogs, expert personnel for liver surgery, histochemical and morphological hepatic pathology, and determination of both therapeutic levels and toxic profiles of immunosuppressive agents, transportation of dogs for experimental procedures, and storage of plasmas, gross specimens, preserved tissues, and molecular materials (DNA, RNA, constructs, cell lines, etc.) from experimental and control dogs. These hemophilic dogs with the accompanying professional and technical support are a unique resource for basic studies focused on developing methods for gene therapy of hemophilia and testing novel gene expression and transfer vectors.
| French, Robert A; Samelson-Jones, Benjamin J; Niemeyer, Glenn P et al. (2018) Complete correction of hemophilia B phenotype by FIX-Padua skeletal muscle gene therapy in an inhibitor-prone dog model. Blood Adv 2:505-508 |
| Gollomp, Kandace; Lambert, Michele P; Poncz, Mortimer (2017) Current status of blood 'pharming': megakaryoctye transfusions as a source of platelets. Curr Opin Hematol 24:565-571 |
| 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 |
| Sim, Xiuli; Poncz, Mortimer; Gadue, Paul et al. (2016) Understanding platelet generation from megakaryocytes: implications for in vitro-derived platelets. Blood 127:1227-33 |
| Marcos-Contreras, Oscar A; Smith, Shannon M; Bellinger, Dwight A et al. (2016) Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII. Blood 127:565-71 |
| Arruda, V R; Samelson-Jones, B J (2016) Gene therapy for immune tolerance induction in hemophilia with inhibitors. J Thromb Haemost 14:1121-34 |
| High, Katherine A; Anguela, Xavier M (2016) Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet 25:R36-41 |
| Siner, Joshua I; Samelson-Jones, Benjamin J; Crudele, Julie M et al. (2016) Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models. JCI Insight 1:e89371 |
| Zhang, Nanyan; Zhi, Huiying; Curtis, Brian R et al. (2016) CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes. Blood 127:675-80 |
| Lyde, R; Sabatino, D; Sullivan, S K et al. (2015) Platelet-delivered therapeutics. J Thromb Haemost 13 Suppl 1:S143-50 |
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