Targeted gene delivery by tropism-modified adenoviral vectors
Targeted gene delivery by tropism-modified adenoviral vectors
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DOI：
10.1038/nbt1196-1574
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发表时间：
1996-11-01
影响因子：
46.9
通讯作者：
Curiel, DT
中科院分区：
文献类型：
--
作者：
Douglas, JT;Rogers, BE;Curiel, DT
腺病毒载体用于基因治疗的效用目前受到限制，部分原因是腺病毒纤维的细胞受体的广泛分布，这排除了特定细胞类型的靶向。因此，为了开发靶向腺病毒，必须消除内源性病毒嗜性并引入脐嗜性。我们假设这两个目标可以通过采用与细胞特异性配体化学缀合的中和抗纤维抗体或抗体片段来实现。为了测试这一概念，我们选择靶向叶酸受体，其在多种恶性细胞的表面上过表达。因此，我们将叶酸缀合至抗纤维单克隆抗体的中和Fab片段。该Fab-叶酸缀合物与携带荧光素酶报告基因的腺病毒载体复合，并且显示出通过叶酸受体以高效率将腺病毒感染重定向至靶细胞。此外，当与携带单纯疱疹病毒胸苷激酶基因的腺病毒载体复合时，Fab-叶酸缀合物介导过表达叶酸受体的细胞的特异性杀伤。因此，这项工作代表了重组腺病毒载体通过非腺病毒细胞受体重新靶向的第一个证明。
The utility of adenoviral vectors for gene therapy is currently limited due, in part, to the widespread distribution of the cellular receptor for the adenovirus fiber that precludes the targeting of specific cell types. In order to develop a targeted adenovirus, it is therefore necessary both to ablate endogenous viral tropism and to introduce navel tropism. We hypothesized that these two goals could be achieved by employing a neutralizing anti-fiber antibody, or antibody fragment, chemically conjugated to a cell-specific ligand. To test this concept, we chose to target the folate receptor, which is overexpressed on the surface of a variety of malignant cells, Therefore, we conjugated folate to the neutralizing Fab fragment of an anti-fiber monoclonal antibody. This Fab-folate conjugate was complexed with an adenoviral vector carrying the luciferase reporter gene and was shown to redirect adenoviral infection ob target cells via the folate receptor at a high efficiency Furthermore, when complexed with an adenoviral vector carrying the gene for herpes simplex virus thymidine kinase, the Fab-folate conjugate mediated the specific killing of cells that overexpress the folate receptor. This work thus represents the first demonstration of the retargeting of a recombinant adenoviral vector vie a non-adenoviral cellular receptor.