1. ¹Cell Genesys, Inc., 500 Forbes Boulevard, South San Francisco, CA 94080, USA
2. ²Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California at Davis, Davis, CA 95616, USA
3. ³Brain Tumor Research Center, University of California at San Francisco, San Francisco, CA 94143, USA

Correspondence: Thomas C. Harding, Fax: +1 650 266 2900. E-mail: thomash@cellgenesys.com

Received 22 June 2005; Revised 6 February 2006; Accepted 6 February 2006.

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.