Journal
GENE THERAPY
Volume 8, Issue 17, Pages 1347-1353Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3301515
Keywords
CAR; adenovirus; vector; biodistribution
Categories
Funding
- NCI NIH HHS [N01 CO-97110, P50 CA83591, P50 CA89019, R01 CA74242, R01 CA83821, R01 CA8688-01] Funding Source: Medline
- NHLBI NIH HHS [R01 HL50255] Funding Source: Medline
- NIDDK NIH HHS [U19 DK57858] Funding Source: Medline
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Intravenous administration of adenoviral vectors results mostly in hepatocyte transduction and subsequent hepatotoxicity. Because hepatocytes express high levels of the primary adenovirus receptor CAR, untargeting hepatocytes requires CAR-binding ablation. The amino acid residues of the viral fiber responsible for CAR-binding are known. We have constructed a mutant adenoviral vector unable to bind CAR and studied vector biodistribution and hepatotoxicity after intravenous administration. In contrast to a vector with wild-type fiber, the infectivity of the CAR-ablated vector is greatly reduced and not susceptible to inhibition with wild-type knob. Biodistribution and hepatotoxicity are, however, not affected by CAR-binding ablation. A possible explanation could be related to an increased blood persistence detected for the CAR-ablated vectors combined with their residual infectivity through other receptors.
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