title: Persistent suppression of ocular neovascularization with intravitreal administration of AAVrh.10 coding for bevacizumab.
abstract: Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. Bevacizumab, an anti-VEGF monoclonal antibody, is efficacious for these disorders, but requires monthly intravitreal administration, with associated discomfort, cost, and adverse event risk. We hypothesized that a single intravitreal administration of adeno-associated virus (AAV) vector expressing bevacizumab would result in persistent eye expression of bevacizumab and suppress VEGF-induced retinal neovascularization. We constructed an AAV rhesus serotype rh.10 vector to deliver bevacizumab (AAVrh.10BevMab) and assessed its ability to suppress neovascularization in transgenic mice overexpressing human VEGF165 in photoreceptors. Intravitreal AAVrh.10BevMab directed long-term bevacizumab expression in the retinal pigmented epithelium. Treated homozygous mice had reduced levels of neovascularization, with 90±4% reduction 168 days following treatment. Thus, a single administration of AAVrh.10BevMab provides long-term suppression of neovascularization without the costs and risks associated with the multiple administrations required for the current conventional bevacizumab monoclonal drug delivery.
authors.affiliation: Department of Respiratory Medicine, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Yanxiong
authors.initials: Y
authors.lastname: Mao
authors.forename: Szilard
authors.initials: S
authors.lastname: Kiss
authors.forename: Julie L
authors.initials: JL
authors.lastname: Boyer
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Jianping
authors.initials: J
authors.lastname: Qiu
authors.forename: Andrew
authors.initials: A
authors.lastname: Carbone
authors.forename: Jason G
authors.initials: JG
authors.lastname: Mezey
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kaminsky
authors.forename: Donald J
authors.initials: DJ
authors.lastname: D'Amico
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D000229:Dependovirus / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006720:Homozygote; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D014822:Vitreous Body / Q000503:physiopathology
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab