Hemophilia A and B are X-linked monogenic disorders caused by deficiencies in
coagulation factor VIII (FVIII) and
factor IX (FIX), respectively. Current treatment for
hemophilia involves
intravenous infusion of
clotting factor concentrates. However, this does not constitute a cure, and the development of gene-based
therapies for
hemophilia to achieve prolonged high level expression of
clotting factors to correct the
bleeding diathesis are warranted. Different types of viral and nonviral gene delivery systems and a wide range of different target cells, including hepatocytes, skeletal muscle cells, hematopoietic stem cells (HSCs), and endothelial cells, have been explored for
hemophilia gene therapy. Adeno-associated virus (AAV)-based and lentiviral vectors are among the most promising vectors for
hemophilia gene therapy. Stable correction of the
bleeding phenotypes in
hemophilia A and B was achieved in murine and canine models, and these promising preclinical studies prompted clinical trials in patients suffering from severe
hemophilia. These studies recently resulted in the first demonstration that long-term expression of therapeutic FIX levels could be achieved in patients undergoing gene therapy. Despite this progress, there are still a number of hurdles that need to be overcome. In particular, the FIX levels obtained were insufficient to prevent
bleeding induced by
trauma or injury. Moreover, the gene-modified cells in these patients can become potential targets for immune destruction by effector T cells, specific for the AAV vector
antigens. Consequently, more efficacious approaches are needed to achieve full
hemostatic correction and to ultimately establish a cure for
hemophilia A and B.