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
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.
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,
Trobridge G, Josephson NC, Vassilopoulos G, Mac J, Russell DW: Improved foamy
virus vectors with minimal viral sequences. Molecular Therapy
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.
Russell DW: Foamy virus vector production and transduction of
hematopoietic cells, in Gene
Transfer: Delivery and Expression of DNA and RNA, A Laboratory Manual,
Cold Spring Harbor Laboratory Press, 2007.
P, Romen F, Liu W, Wirtz R, Koch U, Josephson N, Langbein S,
Lochelt M: Construction and characterizatin of efficient, stable,
and safe replication-deficient foamy virus vectors. Gene Therapy
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.