Research of gene transfer into nonhuman promates using novel types of adenovirus vectors

使用新型腺病毒载体将基因转移到非人类原始动物中的研究

• 批准号: 17390047
• 负责人: MIZUGUCHI Hiroyuki
• 金额: $ 10.23万
• 依托单位: National Institute of Biomedical Innovation
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390047/
• 关键词: adenovirus vector; gene therapy; nonhuman primates; CD46; 受容体; サイトカイン

Adenovirus(Ad) serotype 35(Ad35) vectors are promising gene delivery vehicles. However, the transduction profiles of Ad35 vectors in conventional mice allow a limited estimation of transduction properties of Ad35 vectors due to the restricted expression of the mouse analog of the subgroup B Ad receptor, CD46, in the testis. To properly assess the transduction properties of Ad35 vectors, 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 cynomolgus monkey cells were efficiently transduced with Ad35 vectors. By contrast, Ad35 vector-mediated transduction was hardly found in the all organs, although Ad35 vector genomes were detected in vanous organs following intravenous administration. Less severe histopathological abnormalities were found in the Ad35 vector-infused monkeys compared with the conventional Ad serotype 5(Ad5) vector-injected monke … More ys, in which serious tissue damages 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 decreases in CD16^+ cells and CD20^+ cells) in peripheral blood cells postinjection.Furthermore, Ad35 vectors were locally injected into the organs. Ad35 vectors exhibited unique transduction patterns depending on the organs. Hepatocytes and microglia were mainly transduced with Ad35 vectors after injection into the liver and brain, respectively. Intramuscular injection of Ad35 vectors resulted in transduction of cells which appealed to be fibroblasts and macrophages. Conjunctival epithelial cells express transgene expression following infusion into the vitreous body of eyeball. In these organs, transgene expression was limited to areas around the injection points. Transgene expression was not found in the organs which did not receive Ad35 vector injection. These results suggest that Ad35 vectors would be a preferable gene delivery vehicle by direct administration in the organs. Less

腺病毒(Ad)血清35型(Ad35)载体是一种很有前途的基因载体。然而，由于B亚组Ad受体的小鼠类似物CD46在睾丸中的有限表达，传统小鼠中Ad35载体的转导谱允许对Ad35载体的转导特性进行有限的估计。为了正确评估Ad35载体的转导特性，我们用食蟹猴进行了转导实验，食蟹猴以类似于人类的模式普遍表达CD46。体外转导实验表明，Ad35载体能有效地转导食蟹猴细胞。静脉注射Ad35载体后，各脏器中均可检测到Ad35载体的基因组，而Ad35载体介导的转导在所有器官中几乎未见。与传统的Ad5(Ad5)载体注射猴…相比，注射Ad35载体的猴的组织病理学异常较轻诱发严重的组织损伤和炎症反应，如肝细胞坏死和结肠淋巴组织增生。Ad35和Ad5载体注射后外周血细胞出现相似的血液学改变(CD3^+细胞增多，CD16^+细胞和CD20^+细胞减少)。Ad35载体在不同器官中表现出独特的转导模式。肝细胞和小胶质细胞分别注射入肝和脑后，主要由Ad35载体转导。肌肉注射Ad35载体可诱导细胞转导为成纤维细胞和巨噬细胞。结膜上皮细胞在注入眼球玻璃体后表达转基因。在这些器官中，转基因表达仅限于注射点周围区域。未接受Ad35载体注射的器官中未见转基因表达。这些结果表明，Ad35载体可能是一种通过器官直接给药的较好的基因输送载体。较少

项目成果

新しいアデノウイルスベクターの開発

新型腺病毒载体的开发

• 发表时间: 2006
• 期刊: バイオサイエンスとインダストリー 64(5)
• 作者: Fuminori Sakurai;et. al.;櫻井文教・水口裕之
• 通讯作者: 櫻井文教・水口裕之

Evaluation of adenovirus serotype 35 vector-mediated gene transfer in cynomolgus monkeys.

腺病毒血清型 35 载体介导的食蟹猴基因转移的评估。

• 发表时间: 2006
• 作者: Fuminori Sakurai;Kimiyo Akatomo;Kenji Kawabata;Shin-ichiro Nakamura;Hiroaki Shibata;Kenji Terao;Takao Hayakawa;Hiroyuki Mizuguchi
• 通讯作者: Hiroyuki Mizuguchi

Transduction properties of adenovirus serotype 35 vectors after intravenous administration into nonhuman primates

• DOI: 10.1038/mt.2008.19
• 发表时间: 2008-04-01
• 期刊: MOLECULAR THERAPY
• 影响因子: 12.4
• 作者: Sakurai, Fuminori;Nakamura, Shin-ichiro;Mizuguchi, Hiroyuki
• 通讯作者: Mizuguchi, Hiroyuki

カニクイザルにおける35型アデノウイルスベクターの遺伝子導入特性

35型腺病毒载体在食蟹猴体内的基因转移特性

• 发表时间: 2007
• 作者: 櫻井文教;他
• 通讯作者: 他

Transduction properties of adenovirus serotype 35 vectors in cynomolgus monkeys.

腺病毒血清型 35 载体在食蟹猴中的转导特性。

• 发表时间: 2007
• 作者: Fuminori Sakurai;Kimiyo Akitomo;Kenji Kawabata;Shin-ichiro Nakamura;Hiroaki Shibata;Keiji Terao;Takao Hayakawa;Hiroyuki Mizuguchi
• 通讯作者: Hiroyuki Mizuguchi