Retargeting of adenoviral vector using basic fibroblast growth factor ligand for malignant glioma gene therapy

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  • 1 Department of Pediatrics, University of Southern California School of Medicine; Departments of Neurosurgery and Pathology, Departments of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California; Institute for Clinical Chemistry and Laboratory Diagnostics, Medical School, Heinrich-Heine University, Düsseldorf, Germany; Selective Genetics, Inc., San Diego, California; School of Medicine, Hokkaido University, Sapporo, Japan; and Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, California
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Object. Adenovirus vector (AdV)—mediated gene delivery has been recently demonstrated in clinical trials as a novel potential treatment for malignant gliomas. Combined coxsackievirus B and adenovirus receptor (CAR) has been shown to function as an attachment receptor for multiple adenovirus serotypes, whereas the vitronectin integrins (αvβ3 and αvβ5) are involved in AdV internalization. In resected glioma specimens, the authors demonstrated that malignant gliomas have varying levels of CAR, αvβ3, and αvβ5 expression.

Methods. A correlation between CAR expression and the transduction efficiency of AdV carrying the green fluorescent protein in various human glioblastoma multiforme (GBM) cell lines and GBM primary cell lines was observed. To increase transgene activity in in vitro glioma cells with low or deficient levels of CAR, the authors used basic fibroblast growth factor (FGF2) as a targeting ligand to redirect adenoviral infection through its cognate receptor, FGF receptor 1 (FGFR1), which was expressed at high levels by all glioma cells. These findings were confirmed by in vivo study data demonstrating enhanced transduction efficiency of FGF2-retargeted AdV in CAR-negative intracranial gliomas compared with AdV alone, without evidence of increased angiogenesis.

Conclusions. Altogether, the results demonstrated that AdV-mediated gene transfer using the FGF2/FGFR system is effective in gliomas with low or deficient levels of CAR and suggested that FGF2-retargeting of AdV may be a promising approach in glioma gene therapy.

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Contributor Notes

Address reprint requests to: Thomas C. Chen, M.D., Ph.D., Department of Neurosurgery and Pathology, University of Southern California, 1200 North State Street, #5046, Los Angeles, California 90033. email: TChen68670@aol.com.
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