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TRANSLATIONAL AND CLINICAL RESEARCH

Mesenchymal Stem Cells Effectively Deliver an Oncolytic Adenovirus to Intracranial Glioma

^aBrain Tumor Center, University of Chicago, Chicago, Illinois, USA;
^bDivision of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA;
^cDepartment of Cellular Biology and Anatomy, Louisiana Health Sciences Center, Shreveport, Louisiana, USA

Key Words. Glioma • Stem cells • Adenovirus • Oncolytic virus • Vector • Migration • Gene therapy

Correspondence: Maciej S. Lesniak, M.D., University of Chicago, Section of Neurosurgery, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA. Telephone: 773-834-4757; Fax: 773-834-2608; e-mail: mlesniak{at}surgery.bsd.uchicago.edu

Received September 10, 2007; accepted for publication January 3, 2008.
First published online in STEM CELLS EXPRESS   January 10, 2008.



Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4–5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4–5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4–5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.

Disclosure of potential conflicts of interest is found at the end of this article.