The size of sinusoidal fenestrae is a critical determinant of hepatocyte transduction after adenoviral gene transfer
- 22 July 2004
- journal article
- research article
- Published by Springer Nature in Gene Therapy
- Vol. 11 (20) , 1523-1531
- https://doi.org/10.1038/sj.gt.3302326
Abstract
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 α1-antitrypsin promoter-driven expression cassette (AdAT4). Intravenous administration of 4 × 1012 particles/kg of AdAT4 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.Keywords
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