CURRENT CLINICAL INTERESTS
General hematology/oncology, coagulopathies, thrombosis
CURRENT RESEARCH
INTERESTS
Stem cell gene therapy, tolerance Induction to factor VIII in
hemophilia
RESEARCH DESCRIPTION
Research in the Josephson lab is focused on two areas:
1. Hematopoietic Stem Cell Gene Therapy with Foamy Virus Vectors. Foamy viruses (FV) are non-pathogenic integrating viruses of the spumavirus family. 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. The mouse model of CAMT has both the stem cell and platelet deficits seen in the human disorder and is therefore the focus of our preclinical studies.
2. Induction of Immune Tolerance to Factor VIII by Tolerogenic Dendritic Cells.
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 a less reliable hemostatic profile. 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 to regulatory T cells by immature unactivated
DCs.
SELECTED
PUBLICATIONS
Josephson NC, Trobridge G, Russell DW: Transduction of long-term and mobilized peripheral blood-derived NOD/SCID repopulating cells by foamy virus vectors.
Human Gene Therapy 15(1):87-92, 2004.
Trobridge G, Josephson NC, Vassilopoulos G, Mac J, Russell DW:
Improved foamy virus vectors with minimal viral sequences. Molecular Therapy
6(3):321-8, 2002.
Josephson NC, Vassilopoulos G, Trobridge GD, Priestley GV, Papayannopoulou T, Wood BL, Russell DW: Transduction of human NOD/SCID-repopulating cells with both lymphoid and myeloid potential by foamy virus vectors.
Proc. Natl. Acad. Sci. 99(12): 8295-8300, 2002.
Trobridge G, Vassilopoulos G, Josephson NC, Russell DW: Gene transfer with foamy virus vectors.
Methods in Enzymology 346: 628-648, 2002.
Vassilopoulos G, Trobridge G, Josephson NC, Russell
DW: Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors.
Blood 98(3): 604-609, 2001.
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