Journal
GENE THERAPY
Volume 11, Issue 20, Pages 1523-1531Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3302326
Keywords
adenovirus; apolipoprotein A-I; fenestrae; TEM
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The hepatotropism and intrahepatic distribution of adenoviral vectors may be species dependent. Hepatocyte transduction was evaluated in three rabbit strains after transfer with E1E3E4-deleted adenoviral vectors containing a hepatocyte specific alpha(1)-antitrypsin promoter-driven expression cassette (AdAT(4)). Intravenous administration of 4 x 10(12) particles/kg of AdAT(4) induced human apo A-I levels above 40 mg/dl in Dutch Belt, but below 1 mg/dl in New Zealand White and Fauve de Bourgogne rabbits. Diameters of sinusoidal fenestrae were significantly ( P = 0.0014) larger in Dutch Belt (124 +/- 3.4 nm) than in New Zealand White (108 +/- 1.3 nm) and Fauve de Bourgogne (105 +/- 2.6 nm) rabbits, suggesting that a smaller size constitutes a barrier for hepatocyte transduction. Indeed, intraportal transfer preceded by intraportal injection of sodium decanoate, which increases the diameter of sinusoidal fenestrae to 123 +/- 3.4 nm ( P<0.01) in New Zealand White rabbits, increased human apo A-I levels 32- and 120-fold in New Zealand White and Fauve de Bourgogne rabbits, respectively, but did not affect expression in Dutch Belt rabbits. In conclusion, size of sinusoidal fenestrae appears to be a critical determinant of hepatocyte transduction after adenoviral transfer.
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