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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-10-3050.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3924-3932
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Neonatal or hepatocyte growth factor-potentiated adult gene
therapy with a retroviral vector results in therapeutic levels of
canine factor IX for hemophilia B
Lingfei Xu,
Cuihua Gao,
Mark S. Sands,
Shi-Rong Cai,
Timothy C. Nichols,
Dwight A. Bellinger,
Robin A. Raymer,
Stephanie McCorquodale, and
Katherine Parker Ponder
From the Departments of Internal Medicine,
Biochemistry, Molecular Biophysics, and Genetics, Washington University
School of Medicine, St Louis, MO; and the Department of Pathology and
Laboratory Medicine, University of North Carolina, Chapel Hill.
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 µg/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.
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