CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors
CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors
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DOI：
10.1038/sj.gt.3301515
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发表时间：
2001-09-01
期刊：
影响因子：
5.1
通讯作者：
Curiel, DT
中科院分区：
文献类型：
--
作者：
Alemany, R;Curiel, DT
腺病毒载体的静脉内施用主要导致肝细胞转导和随后的肝毒性。由于肝细胞表达高水平的初级腺病毒受体 CAR，因此非靶向肝细胞需要 CAR 结合消融。负责 CAR 结合的病毒纤维的氨基酸残基是已知的。我们构建了无法结合CAR的突变腺病毒载体，并研究了载体静脉注射后的生物分布和肝毒性。与野生型纤维载体相比，CAR 消除载体的感染性大大降低，并且不易受到野生型旋钮的抑制。然而，生物分布和肝毒性不受 CAR 结合消融的影响。一种可能的解释可能与检测到的 CAR 消除载体的血液持久性增加及其通过其他受体的残留感染性有关。
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.