Hemophilia B is a
bleeding disorder resulting from
factor IX (FIX) deficiency that might be treated with gene therapy. Neonatal delivery would correct the disease sooner than would transfer into adults, and could reduce immunological responses. Neonatal mice were injected intravenously with a Moloney murine leukemia virus-based retroviral vector (RV) expressing canine FIX (cFIX). They achieved 150% to 280% of normal cFIX
antigen levels in plasma (100% is 5 microg/mL), which was functional in vitro and in vivo. Three newborn
hemophilia B dogs that were injected intravenously with RV achieved 12% to 36% of normal cFIX
antigen levels, which improved coagulation tests. Only one mild bleed has occurred during 14 total months of evaluation. This is the first demonstration of prolonged expression after neonatal gene therapy for
hemophilia B in mice or dogs. Most animals failed to make
antibodies to cFIX, demonstrating that neonatal gene transfer may induce tolerance. Although hepatocytes from newborns replicate, those from adults do not. Adult mice therefore received
hepatocyte growth factor to induce hepatocyte replication prior to
intravenous injection of RV. This resulted in expression of 35% of normal cFIX
antigen levels for 11 months, although all mice produced anti-cFIX
antibodies. This is the first demonstration that high levels of FIX activity can be achieved with an RV in adults without a partial
hepatectomy to induce hepatocyte replication. We conclude that RV-mediated hepatic gene therapy is effective for treating
hemophilia B in mice and dogs, although the immune system may complicate gene transfer in adults.