Retargeting of adenoviral vector using basic fibroblast growth factor ligand for malignant glioma gene therapy.
OBJECTIVE
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.
Wang
Weijun
W
Department of Pediatrics, University of Southern California School of Medicine, Los Angeles 90033, USA.
Zhu
Nian-Ling
NL
Chua
Jason
J
Swenson
Steve
S
Costa
Fritz K
FK
Schmitmeier
Stephanie
S
Sosnowski
Barbara A
BA
Shichinohe
Toshiaki
T
Kasahara
Noriyuki
N
Chen
Thomas C
TC
D000256:Adenoviridae / Q000235:genetics*; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D018390:Gene Targeting; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D014161:Transduction, Genetic
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D039302:Integrin alphaVbeta3; D016023:Integrins; D008024:Ligands; D011991:Receptors, Virus; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2