Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma Journal Article
| Authors: | Hicks, M. J.; Funato, K.; Wang, L.; Aronowitz, E.; Dyke, J. P.; Ballon, D. J.; Havlicek, D. F.; Frenk, E. Z.; De, B. P.; Chiuchiolo, M. J.; Sondhi, D.; Hackett, N. R.; Kaminsky, S. M.; Tabar, V.; Crystal, R. G. |
| Article 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. |
| Keywords: | immunohistochemistry; cancer survival; controlled study; gene sequence; human cell; bevacizumab; cancer growth; nonhuman; nuclear magnetic resonance imaging; polymerase chain reaction; mouse; animal tissue; mus; reverse transcription polymerase chain reaction; tumor volume; animal experiment; animal model; tumor xenograft; enzyme linked immunosorbent assay; gene transfer; viral gene delivery system; gene vector; survival time; dna modification; messenger rna; quantitative analysis; contrast enhancement; glioblastoma; western blotting; antiangiogenic therapy; nerve cell; volumetry; gadolinium pentetate meglumine; limit of detection; adeno-associated virus; human; female; priority journal; article |
| Journal Title: | Cancer Gene Therapy |
| Volume: | 22 |
| Issue: | 1 |
| ISSN: | 0929-1903 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-01-01 |
| Start Page: | 1 |
| End Page: | 8 |
| Language: | English |
| DOI: | 10.1038/cgt.2014.58 |
| PROVIDER: | scopus |
| PMCID: | PMC4293257 |
| PUBMED: | 25501993 |
| DOI/URL: | |
| Notes: | Export Date: 2 March 2015 -- Source: Scopus |
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