1. ¹Department of Neurology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA
2. ²Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht, The Netherlands
3. ³Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands
4. ⁴Molecular Neuro-oncology Laboratory, Harvard Medical School, Boston, Massachusetts, USA
5. ⁵Department of Pathology Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Miguel Sena-Esteves, Department of Neurology, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts, 02129 USA. E-mail: msesteves@partners.org

^†Current address: Cancer Biology and Epigenomics Program, Children's Memorial Research Center and Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA

Received 2 April 2008; Accepted 8 July 2008; Published online 19 August 2008.

Abstract

Glioblastoma multiforme (GBM) is a devastating form of brain cancer for which there is no effective treatment. Here, we report a novel approach to brain tumor therapy through genetic modification of normal brain cells to block tumor growth and effect tumor regression. Previous studies have focused on the use of vector-based gene therapy for GBM by direct intratumoral injection with expression of therapeutic proteins by tumor cells themselves. However, as antitumor proteins are generally lethal to tumor cells, the therapeutic reservoir is rapidly depleted, allowing escape of residual tumor cells. Moreover, it has been difficult to achieve consistent transduction of these highly heterogeneous tumors. In our studies, we found that transduction of normal cells in the brain with an adeno-associated virus (AAV) vector encoding interferon- (IFN-) was sufficient to completely prevent tumor growth in orthotopic xenograft models of GBM, even in the contralateral hemisphere. In addition, complete eradication of established tumors was achieved through expression of IFN- by neurons using a neuronal-restricted promoter. To our knowledge this is the first direct demonstration of the efficacy of targeting gene delivery exclusively to normal brain cells for brain tumor therapy.