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Sustained expression of therapeutic levels of human factor VIII in mice
S Connelly, JM Gardner, RM Lyons, A McClelland and M Kaleko
Department of Molecular & Cell Biology, Genetic Therapy, Inc,
Gaithersburg, MD 20878, USA.
Deficiency of coagulation factor VIII (FVIII) results in hemophilia A, a
common hereditary bleeding disorder. Using a human FVIII-encoding
adenoviral vector, Av1ALAPH81, we have demonstrated expression of
therapeutic levels of human FVIII in mice sustained for more than 5 months
after vector administration. Administration of a high dose (4 x 10(9)
plaque-forming units [pfu]) of Av1ALAPH81 to mice resulted in a peak
expression of 2,063 ng/mL of human FVIII in the mouse plasma, with levels
decreasing to background by weeks 15 to 17. Normal FVIII levels in humans
range from 100 to 200 ng/mL and therapeutic levels are as low as 10 ng/mL.
Alternatively, administration of 8- to 80-fold lower vector doses (5 x
10(8) pfu to 5 x 10(7) pfu) to normal adult mice resulted in expression of
FVIII at therapeutic levels sustained for at least 22 weeks. Detailed
analysis of vector toxicity indicated that the high vector dose caused a
dramatic elevation of liver-specific enzyme levels, whereas an eight-fold
lower vector dose was significantly less hepatotoxic. The data presented
here demonstrate that administration of lower, less toxic vector doses
allow long-term persistence of FVIII expression.
Volume 87,
Issue 11,
pp. 4671-4677,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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