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Adeno-Associated Viral Vector-Mediated Gene Transfer of Human Blood
Coagulation Factor IX Into Mouse Liver
Hiroyuki Nakai,
Roland W. Herzog,
J. Nathan Hagstrom,
Johannes Walter,
Szu-Hao Kung,
Edmund Y. Yang,
Shing Jen Tai,
Yuichi Iwaki,
Gary J. Kurtzman,
Krishna J. Fisher,
Peter Colosi,
Linda B. Couto, and
Katherine A. High
From Avigen, Inc, Alameda, CA; the Department of Urology, University
of Southern California School of Medicine, Los Angeles, CA; the
Departments of Pediatrics, Pathology, and Molecular and Cellular
Engineering, University of Pennsylvania School of Medicine,
Philadelphia, PA; the Department of Surgery, The Children's Hospital
of Philadelphia, Philadelphia, PA; and the Institute for Human Gene
Therapy, University of Pennsylvania, Philadelphia, PA.
Recombinant adeno-associated virus vectors (AAV) were prepared in
high titer (1012 to 1013 particles/mL) for the
expression of human factor IX after in vivo transduction of murine
hepatocytes. Injection of AAV-CMV-F.IX (expression from the human
cytomegalovirus IE enhancer/promoter) into the portal vein of adult
mice resulted in no detectable human factor IX in plasma, but in mice
injected intravenously as newborns with the same vector, expression was
initially 55 to 110 ng/mL. The expression in the liver was mostly
transient, and plasma levels decreased to undetectable levels within 5 weeks. However, long-term expression of human F.IX was detected by
immunofluorescence staining in 0.25% of hepatocytes 8 to 10 months
postinjection. The loss of expression was likely caused by suppression
of the CMV promoter, because polymerase chain reaction data showed no
substantial loss of vector DNA in mouse liver. A second vector in which
F.IX expression was controlled by the human EF1 promoter was
constructed and injected into the portal vein of adult C57BL/6 mice at
a dose of 6.3 × 1010 particles. This resulted in
therapeutic plasma levels (200 to 320 ng/mL) for a period of at least 6 months, whereas no human F.IX was detected in plasma of mice injected
with AAV-CMV-F.IX. Doses of AAV-EF1-F.IX of 2.7 × 1011
particles resulted in plasma levels of 700 to 3,200 ng/mL.
Liver-derived expression of human F.IX from the AAV-EF1-F.IX vector
was confirmed by immunofluorescence staining. We conclude that
recombinant AAV can efficiently transduce hepatocytes and direct stable
expression of an F.IX transgene in mouse liver, but sustained
expression is critically dependent on the choice of promoter.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4600-4607
© 1998 by The American Society of Hematology.
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