Department of Respiratory Medicine, West China Hospital, Sichuan University, Sichuan 610041, China.
Hum Gene Ther. 2011 Dec;22(12):1525-35. doi: 10.1089/hum.2011.090. Epub 2011 Oct 27.
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.
血管内皮生长因子 (VEGF) 在新生血管性年龄相关性黄斑变性和糖尿病性视网膜病变的发病机制中起重要作用。贝伐单抗是一种抗 VEGF 的单克隆抗体，对这些疾病有效，但需要每月进行玻璃体内注射，存在相关不适、费用和不良事件风险。我们假设单次玻璃体内给予表达贝伐单抗的腺相关病毒 (AAV) 载体可导致贝伐单抗在眼内持续表达，并抑制 VEGF 诱导的视网膜新生血管形成。我们构建了一种表达贝伐单抗的恒河猴血清型 rh.10 AAV 载体（AAVrh.10BevMab），并评估其抑制在感光细胞中过表达人 VEGF165 的转基因小鼠中新生血管形成的能力。玻璃体内给予 AAVrh.10BevMab 可使贝伐单抗在视网膜色素上皮中长期表达。经治疗的纯合子小鼠的新生血管化程度降低，治疗后 168 天降低 90±4%。因此，单次给予 AAVrh.10BevMab 可提供长期的新生血管抑制作用，而无需当前常规贝伐单抗单克隆药物递送所需的多次给药的费用和风险。
