Administration of pigment epithelium-derived factor delivered by adeno-associated virus inhibits blood-retinal barrier breakdown in diabetic rats

作者：Yu, Hai; Chen, Lei^*; Jiang, Jing

来源：Molecular Vision, 2010, 16(256): 2384-2394.

• ENDOTHELIAL GROWTH-FACTOR
• INTERCELLULAR-ADHESION MOLECULE-1
• INTRAVITREAL SUSTAINED-RELEASE
• VASCULAR-PERMEABILITY
• MACULAR EDEMA
• VITREOUS LEVELS
• IN-VIVO
• RETINOPATHY
• EXPRESSION
• NEOVASCULARIZATION

Purpose: To evaluate the effect of the recombinant adeno-associated virus (rAAV) vector that expresses human pigment epithelium-derived factor (hPEDF) on reducing blood-retinal barrier (BRB) breakdown in the experimental diabetic rat model.
Methods: Diabetes was induced by an intraperitoneal (i.p.) injection of streptozotocin (STZ) into 10-week-old male Wister rats. rAAV(2)-cytomegalovirus (CMV)-hPEDF was delivered into the right eyes by intravitreal injection on the first day after diabetes induction. The contralateral eyes received intravitreal injection of rAAV(2)-CMV-green fluorescent protein as the paired control. Gene delivery and expression of vascular endothelial growth factor (VEGF), occludin, and intercellular adhesion molecule-1 (ICAM-1) were determined with reverse transciptase PCR or western blotting. BRB breakdown changes were quantified by measuring albumin leakage from retinal blood vessels after an intravenous (i.v.) injection of Evans blue albumin.
Results: Retinal transfection with the hPEDF gene construct led to sustained hPEDF gene expression for 6 months, significantly suppressing VEGF mRNA expression in the retina after 1, 3, and 6 months of diabetes induced by STZ compared with paired controls. Moreover, hPEDF dramatically reduced the levels of retinal ICAM-1 but increased the expression of occludin. Furthermore, BRB breakdown was much lower in hPEDF-injected diabetic animals in comparison with controls after 6 months.
Conclusions: A single intravitreal injection of rAAV(2)-CMV-hPEDF can relieve BRB breakdown in STZ-induced diabetic rats for 6 months. The effect is associated with downregulation of retinal VEGF mRNA and ICAM-1 expression and a reduction in the loss of retinal occludin induced by diabetes. The approach of gene transfer may reduce diabetic macular edema, providing long-term protection for diabetic patients at risk of macular edema.

• 出版日期2010-11-15
• 单位中国医科大学