Sustained expression of therapeutic levels of human factor VIII in mice.
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.
Connelly
S
S
Department of Molecular & Cell Biology, Genetic Therapy, Inc, Gaithersburg, MD 20878, USA.
Gardner
J M
JM
Lyons
R M
RM
McClelland
A
A
Kaleko
M
M
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D005169:Factor VIII / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000201:enzymology; D008111:Liver Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*; D013997:Time Factors
D011993:Recombinant Fusion Proteins; D005169:Factor VIII