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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1594-1599
Sustained expression of human factor VIII in mice using a
parvovirus-based vector
Hengjun Chao,
Lan Mao,
Andrew T. Bruce, and
Christopher E. Walsh
From the UNC Gene Therapy Center, and Department of Medicine,
University of North Carolina at Chapel Hill, Chapel Hill, NC.
Persistent therapeutic levels of human factor VIII (hFVIII) would
signify a major advance in the treatment of hemophilia A. Here we
report sustained expression of hFVIII in immunocompetent mice using
recombinant adeno-associated virus (rAAV) vectors. AAV can stably
transduce liver cells, the target tissue for efficient hFVIII
production. Because of rAAV packaging constraints, we tested 2 constructs using small regulatory elements designed for liver-specific transgene expression linked to B-domain-deleted hFVIII (BDD-hFVIII) cDNA. More than 1012/mL rAAV/BDD-hFVIII virion particles
were generated using a transfection scheme that eliminates adenovirus.
Coatest and APTT assays confirmed the production of functional
BDD-hFVIII protein after transduction of 293 and HepG2 cells. In vivo
experiments were performed in C57BL/6 and NOD/scid mice receiving
1010-11 rAAV/hFVIII particles via portal vein injection.
All C57BL/6 mice tested developed anti-hFVIII antibody. In contrast,
NOD/scid mice expressed hFVIII reaching 27% of normal human plasma
levels. As expected, we could not detect hFVIII antigen from plasma
samples isolated from control animals receiving equivalent doses of
rAAV expressing enhanced green fluorescent protein (EGFP). Transgene mRNA expression was detected primarily in the liver and histologic analysis of the liver revealed no pathologic abnormalities. These results demonstrate a promising approach for treatment of hemophilia A.
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