CURRENT CLINICAL INTERESTS
General hematology/oncology, coagulopathies, thrombosis
Tolerance induction to factor VIII in
hemophilia, gene and cell therapy for inherited blood disorders
Research in the Josephson lab is focused on two areas:
of Immune Tolerance to Factor VIII. 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 develop inhibitory antibodies
to factor VIII (fVIII). At present the only method for elimination of
high titer inhibitors is Immune Tolerance Induction by exposing
patients to repeated doses of fVIII over many months to 2 years.
Unfortunately this therapy is extremely expensive and fails in a high
percentage of patients. Our
lab has ongoing projects in the mouse model of hemophilia A that focus
on developing faster and more reliable methods of immune tolerance
include delivery of fVIII within autologous apoptotic cells, antigen
presentation by tolerogenic dendritic cells, and in
utero exposure to antigen that has been modified to allow it to
cross the placental barrier..
Therapy for Congenital Amegakaryocytic Thrombocytopenia (CAMT). CAMT
is a rare inherited bone marrow failure syndrome caused by loss of
function mutations in Mpl, the receptor for thrombopoietin.
We are working on a project aimed at correcting the
hematopoietic defects in the mouse model of CAMT through the
generation and correction of induced pluripotent stem cells (iPSCs).
Because iPSCs are an unlimited source of stem cells they can be
used to compensate for the loss of hematopoietic stem cells associated
with CAMT. Furthermore,
iPSCs have excellent ex vivo
viability making them amenable to multiple methods of correction
including gene addition and site specific gene targeting.
Similar approaches can also be applied to the development of
clinical treatments for other inherited and acquired marrow failure
Josephson NC, Sabo KM, Abkowitz JL: Transduction of feline hematopoietic cells by oncoretroviral vectors pseudotyped with the subgroup A feline leukemia virus (FeLV-A). Molecular Therapy 2(1): 56-62, 2000.
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.
Trobridge G, Vassilopoulos G, Josephson NC, Russell DW: Gene transfer with foamy virus vectors. Methods in Enzymology 346: 628-648, 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. Proceedings of the National Academy of Sciences 99(12): 8295-8300, 2002. PMC123061.
Trobridge G, Josephson N, Vassilopoulos G, Mac J, Russell DW: Improved foamy virus vectors with minimal viral sequences. Molecular Therapy 6(3):321-8, 2002.
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.
Lannutti BJ, Epp A, Roy J, Chen J, Josephson NC: Incomplete restoration of Mpl expression in the mpl-/- mouse produces paradoxical thrombocytosis and partial correction of the stem cell repopulating defect. Blood 113(8):1778-85, 2009. PMC2647669.
Su RJ, Epp A, Latchman Y, Bolgiano D, Pipe SW, Josephson NC: Suppression of FVIII inhibitor formation in hemophilic mice by delivery of transgene modified apoptotic fibroblasts. Molecular Therapy 18(1): 214-22, 2010. PMC2839230.
Su RJ, Epp A, Feng J, Roy J, Latchman Y, Wu X, Bolgiano D, Josephson NC: Suppression of the Immune Response to FVIII in Hemophilia A Mice by Transgene Modified Tolerogenic Dendritic Cells. Molecular Therapy 19 (10): 1896-1904, 2011. PMC3188741.
Shapiro AD, Ragni MV, Valentino LA, Key NS, Josephson NC, et al: Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood 119(3): 666-72, 2012. PMC3265197.
Powell JS, Josephson NC, Quon D, Ragni MV, Cheng G, Li E, Jiang H, Li L, Dumont JA, Goyal J, Zhang X, Sommer J, McCue J, Barbetti M, Luk A, Pierce GF: Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood 119(13): 3031-7, 2012.
Flaherty LM, Josephson NC: Screening for fall risk in patients with haemophilia. Haemophilia 19(3):e103-9, 2013.
Lewis KB, Hughes RJ, Epstein MS, Josephson NC, Kempton CL, Kessler CM, Key NS, et al: Phenotypes of Allo- and Autoimmune Antibody Responses to FVIII Characterized by Surface Plasmon Resonance. PLoS One 8(5):e61120, 2013. PMC3648518.
Nance D, Nakaya-Fletcher S Bolgiano D, Thompson AR, Josephson NC, Konkle, BA: Factor VIII mutation and desmopressin-responsiveness in 62 patients with mild hemophilia A. Haemophilia, in press.
Roy J, Yoshimura R, Epp A, Richard R, and Josephson NC: Foamy virus transduction of Ba/F3 cells is regulated by cell surface sialic acids. Submitted.
Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino L, Mahlangu J, Josephson NC, et al: Phase 3 Study of Long-Acting Recombinant Factor IXFc in Hemophilia B. Submitted.