Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment
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 ha...
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MDPI AG
2023-01-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/1/182 |
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| author | Ivan D. Osipov Valeriia A. Vasikhovskaia Daria S. Zabelina Sergei S. Kutseikin Antonina A. Grazhdantseva Galina V. Kochneva Julia Davydova Sergey V. Netesov Margarita V. Romanenko |
| author_facet | Ivan D. Osipov Valeriia A. Vasikhovskaia Daria S. Zabelina Sergei S. Kutseikin Antonina A. Grazhdantseva Galina V. Kochneva Julia Davydova Sergey V. Netesov Margarita V. Romanenko |
| author_sort | Ivan D. Osipov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T11:02:00Z |
| format | Article |
| id | doaj.art-3de0d61be4f94d838bfe11f699d11d9b |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T11:02:00Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-3de0d61be4f94d838bfe11f699d11d9b2023-12-01T01:12:14ZengMDPI AGViruses1999-49152023-01-0115118210.3390/v15010182Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer TreatmentIvan D. Osipov0Valeriia A. Vasikhovskaia1Daria S. Zabelina2Sergei S. Kutseikin3Antonina A. Grazhdantseva4Galina V. Kochneva5Julia Davydova6Sergey V. Netesov7Margarita V. Romanenko8Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, RussiaFaculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, RussiaFaculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, RussiaFaculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, RussiaState Research Center of Virology and Biotechnology Vector, 630559 Novosibirsk, RussiaState Research Center of Virology and Biotechnology Vector, 630559 Novosibirsk, RussiaSurgery Department, University of Minnesota, Minneapolis, MN 55455, USAFaculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, RussiaFaculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, RussiaHuman 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.https://www.mdpi.com/1999-4915/15/1/182adenovirus type 6 (HAdV-C6Ad6)oncolytic virusvirotherapyadenoviral genome modificationcloning |
| spellingShingle | Ivan D. Osipov Valeriia A. Vasikhovskaia Daria S. Zabelina Sergei S. Kutseikin Antonina A. Grazhdantseva Galina V. Kochneva Julia Davydova Sergey V. Netesov Margarita V. Romanenko Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment Viruses adenovirus type 6 (HAdV-C6 Ad6) oncolytic virus virotherapy adenoviral genome modification cloning |
| title | Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment |
| title_full | Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment |
| title_fullStr | Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment |
| title_full_unstemmed | Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment |
| title_short | Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment |
| title_sort | development of oncolytic vectors based on human adenovirus type 6 for cancer treatment |
| topic | adenovirus type 6 (HAdV-C6 Ad6) oncolytic virus virotherapy adenoviral genome modification cloning |
| url | https://www.mdpi.com/1999-4915/15/1/182 |
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