In vivo evaluation of an adenoviral vector encoding canine factor VIII: high-level, sustained expression in hemophiliac mice.
Hemophilia A is the most common severe hereditary coagulation disorder and is caused by a deficiency in blood clotting factor VIII (FVIII). Canine hemophilia A represents an excellent large animal model that closely mimicks the human disease. In previous studies, treatment of hemophiliac dogs with an adenoviral vector encoding human FVIII resulted in complete correction of the coagulation defect and high-level FVIII expression [Connelly et al. (1996). Blood 88, 3846]. However, FVIII expression was short term, limited by a strong antibody response directed against the human protein. Human FVIII is highly immunogenic in dogs, whereas the canine protein is significantly less immunogenic. Therefore, sustained phenotypic correction of canine hemophilia A may require the expression of the canine protein. In this work, we have isolated the canine FVIII cDNA and generated an adenoviral vector encoding canine FVIII. We demonstrate expression of canine FVIII in hemophiliac mice at levels 10-fold higher than those of the human protein expressed from an analogous vector. Canine FVIII expression was sustained above human therapeutic levels (50 mU/ml) for at least 1 year in hemophiliac mice.
Gallo-Penn
A M
AM
Genetic Therapy, Inc., a Novartis Company, Gaithersburg, MD 20878, USA.
Shirley
P S
PS
Andrews
J L
JL
Kayda
D B
DB
Pinkstaff
A M
AM
Kaloss
M
M
Tinlin
S
S
Cameron
C
C
Notley
C
C
Hough
C
C
Lillicrap
D
D
Kaleko
M
M
Connelly
S
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D005069:Evaluation Studies as Topic; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006467:Hemophilia A / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
D018076:DNA, Complementary; D005169:Factor VIII