title: Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma.
abstract: The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Department of Neurosurgery Memorial Sloan-Kettering Cancer Center, New York, New York and.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Funato
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiology Weill Cornell Medical College, New York, New York.
authors.forename: Eric
authors.initials: E
authors.lastname: Aronowitz
authors.affiliation: Department of Radiology Weill Cornell Medical College, New York, New York.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Dyke
authors.affiliation: Department of Radiology Weill Cornell Medical College, New York, New York.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Ballon
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: David F
authors.initials: DF
authors.lastname: Havlicek
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Esther Z
authors.initials: EZ
authors.lastname: Frenk
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: De
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Chiuchiolo
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kaminsky
authors.affiliation: Department of Neurosurgery Memorial Sloan-Kettering Cancer Center, New York, New York and.
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
authors.affiliation: Department of Genetic Medicine Weill Cornell Medical College, New York, New York.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics*; D000068258:Bevacizumab; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D009389:Neovascularization, Pathologic / Q000628:therapy*; D009474:Neurons / Q000378:metabolism*; D014161:Transduction, Genetic; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab