title: Enhanced gene transfer efficiency in the murine striatum and an orthotopic glioblastoma tumor model, using AAV-7- and AAV-8-pseudotyped vectors.
abstract: In this study, recombinant AAV vectors pseudotyped with viral capsids derived from AAV serotypes 7 and 8 were evaluated for gene transfer in the murine striatum relative to vectors pseudotyped with AAV serotypes 2, 5, and 6. In comparison with rAAV serotype 2, pseudotyped vectors derived from AAV-7 and AAV-8 have increased transduction efficiency in the murine CNS, with the rank order rAAV-7 > rAAV-8 > rAAV-5 > rAAV-2 = rAAV-6, with all vectors demonstrating a marked tropism for neuronal transduction. Pseudotyped rAAV vector gene transfer in the brain after preimplantation of a murine 4C8 glioblastoma tumor was also evaluated. Efficiency of gene transfer to the orthotopic tumor was increased when using AAV-6, -7, and -8 capsid proteins in comparison with serotype 2, with the order rAAV-8 = rAAV-7 > rAAV-6 > rAAV-2 > rAAV-5. The increased gene transfer efficiency of rAAV vectors pseudotyped with the rAAV-8 capsid also provided enhanced therapeutic efficacy in a mouse model of glioblastoma multiforme, using vectors encoding an inhibitor of the vascular endothelial growth factor pathway. These studies demonstrate that rAAV vectors pseudotyped with capsids derived from AAV serotypes 7 and 8 provide enhanced gene transfer in the murine CNS and may offer increased therapeutic efficacy in the treatment of neurological disease.
authors.affiliation: Cell Genesys, South San Francisco, CA 94080, USA. thomash@cellgenesys.com
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Harding
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dickinson
authors.forename: Byron N
authors.initials: BN
authors.lastname: Roberts
authors.forename: Satya
authors.initials: S
authors.lastname: Yendluri
authors.forename: Melissa
authors.initials: M
authors.lastname: Gonzalez-Edick
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lecouteur
authors.forename: Karin U
authors.initials: KU
authors.lastname: Jooss
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D002213:Capsid; D045744:Cell Line, Tumor; D003342:Corpus Striatum; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000379:methods; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D013045:Species Specificity; D014161:Transduction, Genetic / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor