Transduction properties of adenovirus serotype 35 vectors after intravenous administration into nonhuman primates
Transduction properties of adenovirus serotype 35 vectors after intravenous administration into nonhuman primates
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DOI：
10.1038/mt.2008.19
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发表时间：
2008-04-01
影响因子：
12.4
通讯作者：
Mizuguchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Sakurai, Fuminori;Nakamura, Shin-ichiro;Mizuguchi, Hiroyuki
腺病毒血清型35（Ad35）载体已显示出作为有效基因递送载体的前景。然而，Ad35载体在常规小鼠中的转导概况仅允许对这些载体的转导性质进行有限的估计，因为亚组B Ad受体的小鼠类似物CD 46限于睾丸。为了更全面地评估Ad35载体的转导特性，我们使用食蟹猴进行了转导实验，食蟹猴以与人类相似的模式普遍表达CD46。体外转导实验证明，来自食蟹猴的培养细胞被Ad35载体有效地转导。相比之下，在静脉内给药至活猴后，几乎没有在任何器官中发现Ad35载体介导的转导的任何证据，尽管在各种器官中检测到Ad35载体基因组。较不严重的组织病理学异常中发现的Ad35载体注射的猴子比在传统的Ad5载体注射的猴子。在后者中，诱导严重的组织损伤和炎症反应，例如结肠中的肝细胞坏死和淋巴增生。Ad35和Ad5载体在外周血细胞中引起相似的血液学变化（CD3（+）细胞增加，而CD16（+）细胞和CD20（+）细胞减少）。这些结果将为Ad35载体的临床应用提供有价值的信息。
Adenovirus serotype 35 (Ad35) vectors have shown promise as effective gene delivery vehicles. However, the transduction profiles of Ad35 vectors in conventional mice allow only a limited estimation of transduction properties of these vectors, because the mouse analog of the subgroup B Ad receptor, CD46, is restricted to the testis. In order to assess the transduction properties of Ad35 vectors more completely, we performed transduction experiments using cynomolgus monkeys, which ubiquitously express CD46 in a pattern similar to that in humans. In vitro transduction experiments demonstrated that cultured cells from the cynomolgus monkey were efficiently transduced with Ad35 vectors. In contrast, after intravenous administration into live monkeys hardly any evidence of Ad35 vector mediated transduction was found in any of the organs, although Ad35 vector genomes were detected in various organs. Less severe histopathological abnormalities were found in the Ad35 vector-infused monkeys than in the conventional Ad5 vector-injected monkeys. In the latter, serious tissue damage and inflammatory responses, such as hepatocyte necrosis and lymphatic hyperplasia in the colon, were induced. Both Ad35 and Ad5 vectors caused similar hematological changes (increase in CD3(+) cells, and decrease in CD16(+) cells and CD20(+) cells) in peripheral blood cells. These results should provide valuable information for the clinical application of Ad35 vectors.