AAV serotype 8-mediated gene delivery of a soluble VEGF receptor to the CNS for the treatment of glioblastoma.

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.
Authors	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
Journal	Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 13 Issue 5 Pg. 956-66 (May 2006) ISSN: 1525-0016 [Print] United States
PMID	16580881 (Publication Type: Journal Article)
Chemical References	Receptors, Vascular Endothelial Growth Factor
Topics	Animals Cell Line Cell Line, Tumor Central Nervous System (metabolism) Dependovirus (classification, genetics) Female Gene Transfer Techniques Genetic Therapy (methods) Genetic Vectors Glioblastoma (therapy) Humans Male Mice Mice, Inbred Strains Mice, Nude Neoplasm Transplantation Rats Rats, Nude Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism) Serotyping Solubility Transplantation, Heterologous

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