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Research in the Josephson lab is focused on two areas:
Foamy viruses (FV) are non-pathogenic integrating viruses of the spumavirus family, which is a class of retroviruses distinct from oncoviruses and lentiviruses. In nature they are found in non-human primates and other mammals but not humans. Potential advantages of FV vectors include a wide host range, stable virions that can be concentrated by centrifugation, a double-stranded DNA genome that is reverse transcribed in the vector-producing cells, and the largest packaging capacity of any retrovirus. Previously, we have demonstrated that our FV vector system can generate high titer stocks, free from replication competent virus, capable of efficiently transducing both murine and human hematopoeitic stem cells.
We are interested in developing FV vectors for clinical application in the treatment of inherited blood disorders. Currently, we are concentrating our efforts on developing vectors and stem cell transduction protocols to treat Congenital Amegakaryocytic Thrombocytopenia (CAMT). CAMT is caused by loss of function mutations in Mpl, the receptor for the growth factor thrombopoieitin. Patients born with this disease have very low platelet counts and over the course of months to a few years develop complete bone marrow failure. The only known cure is stem cell transplantation from an HLA matched donor. CAMT is an attractive disease to approach with gene therapy because stem cells corrected with a transgene expressing Mpl will be given a survival advantage. Therefore, it should be possible to cure the disease by transducing only a minority of the stem cells contributing to hematopoiesis. However, because of the inherent stem cell defect in CAMT, procuring adequate numbers of stem cells and maintaining them ex vivo for vector transduction presents a significant challenge. Furthermore, transgene expression needs to be limited to stem cells and cells of the megakaryocyte lineage to avoid the dyshematopoieses that occurs with constitutive Mpl expression. The mouse model of CAMT has both the stem cell and platelet deficits seen in the human disorder and is therefore the model we are focusing on in our preclinical studies.
Infusion of high purity or recombinant human factor concentrates remains the most effective treatment for hemophilia. However, approximately 30% of patients with severe hemophilia A (factor VIII <1%) develop inhibitory antibodies. Furthermore, in half of these patients the inhibitors that develop are persistent and of sufficiently high titer that alternative treatments are needed to effectively control acute bleeding. These alternatives are all considerably more expensive than standard concentrates and have less reliable hemostatic profiles. At present the only method for elimination of high titer inhibitors is Immune Tolerance Induction (ITI) by exposing patients to repeated factor VIII (FVIII) doses over many months to 2 years. Though the exact mechanism of ITI is unknown it produces durable tolerance in treated patients 60-80% of the time. Unfortunately this therapy is extremely expensive, costing in the range of $1 million for the average patient. This project focuses on developing faster and more reliable methods of immune tolerance induction to FVIII, in the mouse model of hemophilia A, through antigen presentation by immature unactivated dendritic cells.
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