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Suppression of Intracranial Human Glioma Growth after Intramuscular Administration of an Adeno-associated Viral Vector Expressing Angiostatin¹

Cancer Institute and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 [H-I. M., P. G., S-Y. C.]; Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 [H-I. M., J. L., X. X.]; and Department of Neurological Surgery and Tri-Service General Hospital, Taipei, Taiwan [H-I. M., Y-H. C.], Neuromedical Scientific Center, Buddhist Tzu-Chi General Hospital, Hualian, Taiwan [S-Z. L.]

Despite various therapeutic interventions, glioblastoma multiforme (GBM) is one of the most highly vascularized neoplasms in humans with poor prognosis. In this study, we show that a single i.m. injection of an adeno-associated viral (AAV) vector expressing angiostatin, a potent angiogenic inhibitor, effectively suppresses human glioma growth in the brain of nude mice. Approximately 40% of the tumor-bearing mice treated with AAV-angiostatin vector survived for >10 months (the duration of the experiments). In contrast, 100% of the tumor-bearing mice in the control groups, with or without i.m. injection of a control vector AAV-GFP, died because of excessive tumor burden by 6 weeks. High levels of angiostatin produced by the AAV vector were detected in blood circulation for >250 days after the one-time vector injection. The secreted angiostatin specifically targeted neovessels in the brain tumors, as evidenced by the diminished vessel densities and increased apoptosis of tumor cells surrounding these neovessels. Our study thus demonstrates that AAV-mediated antiangiogenesis gene therapy offers efficient and sustained systemic delivery of the therapeutic product, which in turn effectively suppresses glioma growth in the brain.

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