Enhanced transduction of malignant glioma with a double targeted Ad5/3-RGD fiber-modified adenovirus.
Malignant brain tumors remain refractory to adenovirus type 5 (Ad5)-based gene therapy, mostly due to the lack of the primary Ad5 receptor, the coxsackie and adenovirus receptor, on brain tumor cells. To bypass the dependence on coxsackie and adenovirus receptor for adenoviral entry and infectivity, we used a novel, double targeted Ad5 backbone-based vector carrying a chimeric Ad5/3 fiber with integrin-binding RGD motif incorporated in its Ad3 knob domain. We then tested the new virus in vitro and in vivo in the setting of malignant glioma. Ad5/3-RGD showed a 10-fold increase in gene expression in passaged cell lines and up to 75-fold increase in primary tumors obtained from patients relative to the control. These results were further corroborated in our in vivo human glioma xenograft model, where the Ad5/3-RGD vector showed a 1,000-fold increase in infectivity as compared with the control. Taken together, our findings indicate that Ad5/3-RGD may be a superior vector for applications in glioma gene therapy and therefore warrants further attention in the field of neuro-oncology.
Tyler
Matthew A
MA
Division of Neurosurgery, The University of Chicago, MC 3026, Chicago, IL 60637, USA.
Ulasov
Ilya V
IV
Borovjagin
Anton
A
Sonabend
Adam M
AM
Khramtsov
Andrey
A
Han
Yu
Y
Dent
Paul
P
Fisher
Paul B
PB
Curiel
David T
DT
Lesniak
Maciej S
MS
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D005434:Flow Cytometry / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid