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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 3968-3975
Adenovirus-Mediated Expression of Human Coagulation Factor IX in
the Rhesus Macaque Is Associated With Dose-Limiting Toxicity
Jay N. Lozier,
Mark E. Metzger,
Robert E. Donahue, and
Richard A. Morgan
From the Clinical Gene Therapy Branch, National Human Genome Research
Institute, Bethesda, MD; and the Hematology Branch, National Heart,
Lung, and Blood Institute, 5 Research Court, Rockville, MD.
We used a first-generation adenovirus vector (AVC3FIX5) to assess
whether human factor IX could be expressed and detected in the rhesus
macaque, which we have shown does not make high-titer antibodies to
human factor IX protein. Three animals received 1 × 1010
to 1 × 1011 plaque-forming units per kilogram by
intravenous injection. Human factor IX was present within 24 hours of
vector administration and peaked 4 days later at 4,000 ng/mL in the
high-dose recipient, and lower levels were seen in the
intermediate-dose recipient. No human factor IX was detected in the
low-dose recipient's plasma. Serum cytokine analysis and early
hypoferremia suggested a dose-dependent acute-phase response to the
vector. Human factor IX was detectable in rhesus plasma for 2 to 3 weeks for the high- and intermediate-dose recipients, but disappeared
concomitant with high-titer antihuman factor IX antibody development.
There was substantial, dose-dependent, dose-limiting liver toxicity
that was manifest as elevated serum transaminase levels,
hyperbilirubinemia, hypoalbuminemia, and prolongation of clotting
times. Of particular interest was prolongation of the thrombin clotting
time, an indicator of decreased fibrinogen or fibrinogen dysfunction.
All evidence of liver toxicity resolved except for persistent
hypofibrinogenemia in the high-dose recipient, indicating possible
permanent liver damage. Our data suggest a narrow therapeutic window
for first-generation adenovirus-mediated gene transfer. The development
of antihuman factor IX antibodies and abnormalities of fibrinogen in
the rhesus macaque is of concern for application of adenovirus (or
other viral) vectors to hemophilia gene therapy.
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