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A novel immunocompetent murine tumor model for the evaluation of RCAd-enhanced RDAd transduction efficacy
Huiping Wang1, Fang Wei, Jufeng Zhang
1Experimental Research Center, First People's Hospital, School of Medicine, Shanghai Jiaotong University, 85 Wujin Road, Shanghai 200080, China.
Abstract:
Low gene transfer rate in tumors, high dose-induced acute inflammatory response, and lack of an immunocompetent preclinical animal model to accurately reflect the therapeutic efficacy are prominent reasons for the lack of clinical success of adenoviral (Ad) vectors. In this study, we tested whether human replication-competent adenovirus (RCAd) can replicate in T739 mouse bladder transitional tumor cells (BTT) and lung adenocarcinoma cells (LA795), and whether RCAd can enhance the transduction rate and transgene expression of human replication defective adenoviruses (RDAd) in these tumor cells in vitro and in vivo. We demonstrated that human RCAd exhibited good infectability and cytopathologic effects in mouse BTT and LA795 cells, which was comparable to that in A549 and NCIH460 human tumor cells. In contrast, no infectability and cytopathologic effects were observed in other three mouse tumor cells such as 4T1, B16, and Lewis cells. The combined use of RCAd with RDAd significantly enhanced RDAd transduction efficiency in BTT and LA795 tumor cells in vitro and in vivo. When BTT and LA795 cells were co-infected with RDAd Ad-EGFP and RCAd, a large amount of E1a expression and 2-3 orders of increases in Ad-EGFP genomic DNA were observed. In contrast, the expression of the late gene Hexon is very low, which may explain ineffective packaging of viral particles. In conclusion, our study provided a novel immunocompetent animal model which is useful for evaluating RCAd infectability, cytopathy, and replication. The combined use of RCAd and RDAd provided a new solution for cancer gene therapy.
Insights
Human replication-competent adenovirus (RCAd) effectively infects specific mouse tumor cells and enhances gene transfer when combined with replication-defective adenoviruses (RDAd), offering a new cancer gene therapy approach.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Adenoviral vectors face challenges in cancer gene therapy, including low tumor gene transfer, inflammation, and lack of suitable animal models.
- Existing models do not accurately reflect therapeutic efficacy in an immunocompetent setting.
Purpose of the Study:
- To evaluate human replication-competent adenovirus (RCAd) infectability and cytopathic effects in mouse bladder transitional tumor (BTT) and lung adenocarcinoma (LA795) cells.
- To determine if RCAd enhances the transduction and transgene expression of replication-defective adenoviruses (RDAd) in these tumor cells.
- To establish a novel immunocompetent animal model for evaluating adenoviral vector efficacy.
Main Methods:
- In vitro and in vivo testing of human RCAd infectability and cytopathic effects in mouse BTT and LA795 cells.
- Co-infection experiments with RCAd and RDAd (Ad-EGFP) in BTT and LA795 cells.
- Assessment of viral gene expression (E1a, Hexon) and genomic DNA levels.
Main Results:
- Human RCAd demonstrated infectability and cytopathic effects in mouse BTT and LA795 cells, comparable to human tumor cells.
- RCAd significantly enhanced RDAd transduction efficiency in BTT and LA795 cells both in vitro and in vivo.
- Co-infection led to increased E1a expression and genomic DNA of Ad-EGFP, but low Hexon expression, suggesting limited viral particle packaging.
Conclusions:
- Human RCAd shows promise for cancer gene therapy, exhibiting infectability in specific mouse tumor models.
- The combination of RCAd and RDAd offers a potential strategy to improve adenoviral gene transfer efficiency in cancer.
- A novel immunocompetent model was developed for evaluating RCAd-based therapies.
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