title: Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model.
abstract: Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors.
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA; Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Matheus Hw
authors.initials: MH
authors.lastname: Crommentuijn
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rami
authors.initials: R
authors.lastname: Kantar
authors.affiliation: Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center , Amsterdam, The Netherlands.
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.affiliation: Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center , Amsterdam, The Netherlands.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Badr
authors.affiliation: Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA; Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Maguire
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous