Work in the Josephson lab comprises general hematology and oncology, coagulopathies, and thrombosis, with current projects in tolerance induction to factor VIII in hemophilia and in gene and cell therapy for inherited blood disorders.
Areas of Study
Induction 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 percent 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 two years. Unfortunately this therapy is extremely expensive and fails in a high percentage of patients. Dr. Josephson's laboratory has ongoing projects in the mouse model of hemophilia A that focus on developing faster and more reliable methods of immune tolerance induction. Approaches include delivery of FVIII antigen by 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.
Gene 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. Dr. Josephson's lab is developing approaches for 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 syndromes.