AAV Serotype 8-Mediated Gene Delivery of a Soluble VEGF Receptor to the CNS for the Treatment of Glioblastoma

Thomas C. Harding, Alshad S. Lalani, Byron N. Roberts, Satya Yendluri, Bo Luan, Kathryn E. Koprivnikar, Melissa Gonzalez-Edick, Guang Huan-Tu, Randy Musterer, Melinda J. VanRoey, Tomoko Ozawa, Richard A. LeCouter, Dennis Deen, Peter J Dickinson, Karin Jooss

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The presence of the blood-brain barrier complicates drug delivery in the development of therapeutic agents for the treatment of glioblastoma multiforme (GBM). The use of local gene transfer in the brain has the potential to overcome this delivery barrier by allowing the expression of therapeutic agents directly at the tumor site. In this study, we describe the development of a recombinant adeno-associated (rAAV) serotype 8 vector that encodes an optimized soluble inhibitor, termed sVEGFR1/R2, of vascular endothelial growth factor (VEGF). VEGF is an angiogenic factor highly up-regulated in GBM tumor tissue and correlates with disease progression. In subcutaneous models of GBM, VEGF inhibition following rAAV-mediated gene transfer significantly reduces overall tumor volume and increases median survival time following a single administration of vector. Using orthotopic brain tumor models of GBM, we find that direct intracranial administration of the rAAV-sVEGFR1/R2 vector to the tumor site demonstrates anti-tumor efficacy at doses that are not efficacious following systemic delivery of the vector. We propose that rAAV-mediated gene transfer of a potent soluble VEGF inhibitor in the CNS represents an effective antiangiogenic treatment strategy for GBM.

Original languageEnglish (US)
Pages (from-to)956-966
Number of pages11
JournalMolecular Therapy
Volume13
Issue number5
DOIs
StatePublished - May 2006

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Keywords

  • adeno-associated virus
  • antiangiogenesis
  • brain cancer
  • gene therapy
  • glioblastoma
  • serotype 8
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Harding, T. C., Lalani, A. S., Roberts, B. N., Yendluri, S., Luan, B., Koprivnikar, K. E., Gonzalez-Edick, M., Huan-Tu, G., Musterer, R., VanRoey, M. J., Ozawa, T., LeCouter, R. A., Deen, D., Dickinson, P. J., & Jooss, K. (2006). AAV Serotype 8-Mediated Gene Delivery of a Soluble VEGF Receptor to the CNS for the Treatment of Glioblastoma. Molecular Therapy, 13(5), 956-966. https://doi.org/10.1016/j.ymthe.2006.02.004