Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment.
Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment.
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DOI：
10.3390/v15010182
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发表时间：
2023-01-07
期刊：
影响因子：
--
通讯作者：
Romanenko MV
中科院分区：
文献类型：
--
作者：
Osipov ID;Vasikhovskaia VA;Zabelina DS;Kutseikin SS;Grazhdantseva AA;Kochneva GV;Davydova J;Netesov SV;Romanenko MV
人腺病毒6型（HAdV-C6）是一个有前途的候选人的发展溶瘤载体，因为它具有低血清阳性率和内在的能力，逃避组织巨噬细胞。然而，由于缺乏方便的克隆方法，其作为治疗剂的进一步发展受到阻碍。我们开发了一种新的技术，将携带具有修饰的E1 A和E3区域的远端基因组部分的穿梭质粒与截短的HAdV-C6基因组在体外重组。利用这种方法，我们已经构建了一种新的Ad 6-hT-GM载体控制的hTERT启动子和表达粒细胞-巨噬细胞集落刺激因子（GM-CSF），而不是6.7K和gp 19 K E3蛋白。我们已经证明，hTERT启动子的控制可能会导致延迟病毒复制，但不会显着改变重组病毒的细胞毒性能力。通过置换E3-6.7K/gp 19 K区域插入转基因不会显著改变E3基因的表达模式;然而，观察到来自主要晚期启动子的表达的轻微变化。最后，我们已经证明，与模拟治疗的小鼠相比，用Ad 6-hT-GM治疗小鼠模型中的人乳腺癌异种移植物显著降低了肿瘤体积并改善了存活时间。
Human Adenovirus type 6 (HAdV-C6) is a promising candidate for the development of oncolytic vectors as it has low seroprevalence and the intrinsic ability to evade tissue macrophages. However, its further development as a therapeutic agent is hampered by the lack of convenient cloning methods. We have developed a novel technology when a shuttle plasmid carrying the distal genome parts with modified E1A and E3 regions is recombined in vitro with the truncated HAdV-C6 genome. Using this approach, we have constructed a novel Ad6-hT-GM vector controlled by the hTERT promoter and expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of 6.7K and gp19K E3 proteins. We have demonstrated that control by the hTERT promoter may result in delayed viral replication, which nevertheless does not significantly change the cytotoxic ability of recombinant viruses. The insertion of the transgene by displacing the E3-6.7K/gp19K region does not drastically change the expression patterns of E3 genes; however, mild changes in expression from major late promoter were observed. Finally, we have demonstrated that the treatment of human breast cancer xenografts in murine models with Ad6-hT-GM significantly decreased the tumor volume and improved survival time compared to mock-treated mice.
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