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Research Articles: Targets

Enhanced transduction of malignant glioma with a double targeted Ad5/3-RGD fiber-modified adenovirus

¹ Division of Neurosurgery and ² Department of Pathology, The University of Chicago, Chicago, Illinois; ³ Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama; ⁴ Departments of Biochemistry/Pharmacology, Toxicology, Physiology, and Radiation Oncology, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and ⁵ Departments of Pathology, Neurosurgery, and Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York

Requests for reprints: Maciej S. Lesniak, Division of Neurosurgery, The University of Chicago, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637. Phone: 773-834-4757; Fax: 773-702-2608. E-mail: mlesniak{at}surgery.bsd.uchicago.edu

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. [Mol Cancer Ther 2006;5(9):2408–17]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ I.V. Ulasov, A.A. Rivera, Y. Han, et al. Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to malignant glioma. Neuro-Oncology 2006; Submitted.

Received 4/ 4/06; revised 5/23/06; accepted 6/29/06.

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