INHIBITOR FORMATION IN GENE THERAPY FOR HEMOPHILIA

Children'S Hospital Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Our laboratory has had a longstanding interest in gene therapy as an approach to treating hemophilia B. Recently we have developed promising data in animal models of hemophilia using AAV-mediated gene transfer into muscle and liver. AAV is particularly attractive as a gene transfer vehicle because it is not associated with a strong immune response to the vector itself. In an engineered mouse model of hemophilia B in which the F.IX gene is deleted, however, successful gene transfer and expression have been accompanied by development of antibodies to the transgene product. In dogs with hemophilia B resulting from a missense mutation in the F.IX gene, antibody formation following AAV-mediated muscle-directed gene transfer has been either absent or transient and low-level. Based on our studies thus far, we hypothesize that the antibody response to the transgene product in AAV- mediated gene transfer will be influenced by the underlying mutation, and that this effect is based on whether or not the mutation allows the development of T cell tolerance. In the proposed studies we will use murine and canine models of hemophilia B to 1) define the role of T helper cells in the immune response to a transgene administered via intramuscular injection of an AAV vector; 2) characterize more fully the immune response to the transgene product in dogs with hemophilia B; and 3) determine whether any of several straightforward clinically feasible maneuvers can be used to modulate the immune response to the transgene product. These studies will involve a collaboration between the P.I.'s lab and the laboratory of Dr. Hildegund Ertl, an immunologist with experience in characterizing immune responses in the setting of viral vectors.