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Retargeting of adenoviral vector using basic fibroblast growth factor ligand for malignant glioma gene therapy
Weijun Wang1, Nian-Ling Zhu, Jason Chua
1Department of Pediatrics, University of Southern California School of Medicine, Los Angeles 90033, USA.
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 (alphavbeta3 and alphavbeta5) are involved in AdV internalization. In resected glioma specimens, the authors demonstrated that malignant gliomas have varying levels of CAR, alphavbeta3, and alphavbeta5 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.
Insights
Adenovirus vector (AdV) gene therapy shows promise for malignant gliomas. Retargeting AdV with FGF2 enhances gene delivery in CAR-negative gliomas, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- Malignant gliomas are a significant challenge in neuro-oncology.
- Adenovirus vectors (AdV) are being explored for gene delivery in glioma treatment.
- Adenovirus entry relies on coxsackievirus and adenovirus receptor (CAR) and integrins (alphavbeta3/alphavbeta5), which vary in gliomas.
Purpose of the Study:
- To investigate the efficacy of AdV-mediated gene delivery in malignant gliomas.
- To explore strategies for enhancing AdV transduction in CAR-deficient gliomas.
- To evaluate the potential of FGF2-retargeted AdV for glioma gene therapy.
Main Methods:
- Assessed CAR, alphavbeta3, and alphavbeta5 expression in glioma specimens.
- Correlated CAR expression with AdV transduction efficiency in GBM cell lines.
- Utilized FGF2 to retarget AdV via FGFR1 for enhanced transduction in low-CAR gliomas.
- Validated findings in vivo using FGF2-retargeted AdV in intracranial gliomas.
Main Results:
- Malignant gliomas exhibit variable expression of CAR and integrins.
- FGF2-retargeting significantly improved AdV transduction in CAR-negative and low-CAR glioma cells in vitro.
- In vivo studies confirmed enhanced transduction of FGF2-retargeted AdV in CAR-negative intracranial gliomas.
- No increased angiogenesis was observed with the retargeted AdV.
Conclusions:
- AdV-mediated gene transfer using the FGF2/FGFR system is effective in gliomas with low or deficient CAR levels.
- FGF2-retargeting of AdV presents a promising strategy for overcoming AdV entry barriers in glioma gene therapy.
- This approach offers a potential advancement for treating challenging malignant gliomas.
