Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma
| Autor: | Bishnu P. De, Maria J. Chiuchiolo, Neil R. Hackett, Jonathan P. Dyke, Esther Z Frenk, Douglas Ballon, Martin J. Hicks, Eric Aronowitz, Ronald G. Crystal, Kosuke Funato, Dolan Sondhi, Lan Wang, Viviane Tabar, Stephen M. Kaminsky, David F. Havlicek |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Bevacizumab medicine.drug_class Genetic enhancement Genetic Vectors Gene Expression bevacizumab Monoclonal antibody Antibodies Monoclonal Humanized adeon-associated virus Article Neovascularization chemistry.chemical_compound Mice Transduction Genetic Medicine Animals Humans Molecular Biology Neurons Neovascularization Pathologic business.industry glioblastoma Brain Dependovirus blood-brain barrier medicine.disease Primary tumor Magnetic Resonance Imaging Xenograft Model Antitumor Assays gene therapy 3. Good health Tumor Burden Vascular endothelial growth factor Disease Models Animal chemistry Monoclonal Molecular Medicine Immunohistochemistry Female medicine.symptom business medicine.drug |
| Zdroj: | Cancer gene therapy |
| ISSN: | 1476-5500 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|