Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, Mori K, Yang H S, Zack D J, Ettyreddy D, Brough D E, Wei L L, Campochiaro P A
The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Cell Physiol. 2001 Aug;188(2):253-63. doi: 10.1002/jcp.1114.
In this study, we investigated whether overexpression of pigment epithelium-derived factor (PEDF) by gene transfer can inhibit neovascularization by testing its effect in three different models of ocular neovascularization. Intravitreous injection of an adenoviral vector encoding PEDF resulted in expression of PEDF mRNA in the eye measured by RT-PCR and increased immunohistochemical staining for PEDF protein throughout the retina. In mice with laser-induced rupture of Bruch's membrane, choroidal neovascularization was significantly reduced after intravitreous injection of PEDF vector compared to injection of null vector or no injection. Subretinal injection of the PEDF vector resulted in prominent staining for PEDF in retinal pigmented epithelial cells and strong inhibition of choroidal neovascularization. In two models of retinal neovascularization (transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors and mice with oxygen-induced ischemic retinopathy), intravitreous injection of null vector resulted in decreased neovascularization compared to no injection, but intravitreous injection of PEDF vector resulted in further inhibition of neovascularization that was statistically significant. These data suggest that sustained increased intraocular expression of PEDF by gene therapy might provide a promising approach for treatment of ocular neovascularization.
在本研究中，我们通过在三种不同的眼部新生血管模型中测试其效果，来研究通过基因转移过表达色素上皮衍生因子（PEDF）是否能够抑制新生血管形成。玻璃体内注射编码PEDF的腺病毒载体，通过逆转录聚合酶链反应（RT-PCR）检测到眼部PEDF信使核糖核酸（mRNA）的表达，并在整个视网膜中增加了PEDF蛋白的免疫组织化学染色。在激光诱导布鲁赫膜破裂的小鼠中，与注射空载体或不注射相比，玻璃体内注射PEDF载体后脉络膜新生血管明显减少。视网膜下注射PEDF载体导致视网膜色素上皮细胞中PEDF染色显著，并强烈抑制脉络膜新生血管形成。在两种视网膜新生血管模型（光感受器中血管内皮生长因子（VEGF）表达增加的转基因小鼠和氧诱导缺血性视网膜病变小鼠）中，与不注射相比，玻璃体内注射空载体导致新生血管减少，但玻璃体内注射PEDF载体导致新生血管进一步受到抑制，且具有统计学意义。这些数据表明，通过基因治疗使眼内PEDF持续增加表达可能为治疗眼部新生血管提供一种有前景的方法。
