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 a denoviral vector, AV1ALAPH81. we have demonstrated expression of thera peutic levels of human FVII in mice sustained for more than 5 months a fter vector administration. Administration of a high dose (4 x 10(9) p laque-forming units [pfu]) of AV1ALAPH81 to mice resulted in a peak ex pression of 2,063 ng/mL of human FVIII in the mouse plasma, with level s decreasing to background by weeks 15 to 17. Normal FVIII levels in h umans 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 v ector dose caused a dramatic elevation of liver-specific enzyme levels . whereas an eightfold lower vector dose was significantly less hepato toxic. The data presented here demonstrate that administration of lowe r, less toxic vector doses allow long-term persistence of FVIII expres sion. (C) 1996 by The American Society of Hematology.