CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors.
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.
Alemany
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Division of Human Gene Therapy, Department of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Curiel
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DT
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000914:Antibodies, Viral / Q000378:metabolism; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015870:Gene Expression; D005822:Genetic Vectors / Q000378:metabolism* / Q000633:toxicity; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000821:virology*; D007275:Injections, Intravenous; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D011991:Receptors, Virus / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution
D000914:Antibodies, Viral; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D008164:Luminescent Proteins; D011991:Receptors, Virus; D049452:Green Fluorescent Proteins