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Combined Genetic and Chemical Capsid Modifications of Adenovirus-Based Gene Transfer Vectors for Shielding and Targeting
Published on: October 26, 2018
Efficient infection of tumor endothelial cells by a capsid-modified adenovirus
K Shinozaki1, E Suominen, F Carrick
1Carl C. Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Abstract:
Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/35 may be useful in anticancer strategies targeting tumor endothelial cells.
Insights
A novel hybrid adenovirus (Ad5/35) effectively targets tumor vasculature, unlike standard adenovirus (Ad5). This enhanced gene therapy vector shows promise for anti-cancer strategies by specifically infecting endothelial cells in tumors with reduced liver toxicity.
Area of Science:
- Oncolytic Virotherapy
- Gene Therapy
- Molecular Biology
Background:
- Targeted antiangiogenic gene therapy offers a promising avenue for metastatic cancer treatment.
- Adenovirus serotype 5 (Ad5) has limitations in targeting endothelial cells due to receptor scarcity, impacting its efficacy.
- Developing vectors that specifically target tumor vasculature is crucial for effective cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of a hybrid Ad5/35 virus in targeting tumor vasculature.
- To compare the targeting capabilities and gene expression efficiency of Ad5/35 with Ad5 in endothelial cells.
- To assess the safety and biodistribution profile of Ad5/35 in a preclinical cancer model.
Main Methods:
- Utilized a hybrid Ad5/35 virus, replacing the Ad5 fiber with serotype 35 fiber.
- Performed infection studies on human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) using Ad5/35 and Ad5 at various multiplicities of infection (MOI).
- Analyzed gene expression levels post-transduction and evaluated viral biodistribution in a rat colon carcinoma tumor model.
Main Results:
- Ad5/35 demonstrated significantly higher transduction efficiency in HUVECs (100%) and HAECs (95% at MOI 3.6) compared to Ad5 (10% at MOI 120).
- Gene expression was 1–3 orders of magnitude higher with Ad5/35 compared to Ad5 in endothelial cells.
- Ad5/35 showed reduced infectivity in liver cells and localized to the tumor vasculature (CD31 and Flk-1 positive cells) in vivo, unlike Ad5 which accumulated in the liver.
Conclusions:
- The hybrid Ad5/35 virus exhibits superior targeting of tumor endothelial cells compared to Ad5.
- Ad5/35 offers a potentially improved safety profile due to reduced liver cell infectivity.
- This Ad5/35 vector holds significant potential for developing novel anti-cancer gene therapies focused on tumor vasculature.
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