AG13764 and AG13711 Reverses VEGF-Induced Choroidal Neovascularization in Rat Eye

AG13764 和 AG13711 逆转 VEGF 诱导的大鼠眼脉络膜新生血管形成

• 批准号: 7968355
• 负责人: Sheldon Miller
• 金额: $ 4.59万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7968355
• 关键词: Age related macular degeneration; Animal Model; Animals; Area; Blindness; Blood Vessels; Choroid; Choroidal Neovascularization; Data; Eye; Eye diseases; Goals; Growth Factor; Histology; Immunohistochemistry; Injection of therapeutic agent; Measures; Methods; Modeling; Morphology; PDGFRB gene; Rattus; Recovery; Retinal; Sclera; Signal Pathway; Signal Transduction; Suspension substance; Suspensions; Therapeutic Intervention; Transgenic Model; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; efficacy testing; fluorescein isothiocyanate dextran; inhibitor/antagonist; interest; novel therapeutic intervention; postnatal; receptor

Purpose: Age-related macular degeneration (AMD) is the major cause of blindness for people over 60. In the wet form of AMD compounds targeting growth factor signaling pathways such as VEGF have been a major focus for therapeutic interventions. In a previously developed rat model of CNV, we utilized two receptor tyrosine kinase inhibitors (RTKi) to block VEGFR-1, VEGFR-2 and PDGFR signaling following the establishment of CNV. Methods: AAV-VEGF165 was injected into the subretinal space of rats at postnatal days 15-17. Six weeks later, a suspension of RTK inhibitors, AG013764 or AG013711, was injected intraperitoneally (IP, twice daily) or intravitreally (every five days) over a two week period. FITC-dextran whole-mounts of RPE-choroid-sclera were prepared after the animals were sacrificed. CNV area was quantified using Neurolucida to measure the hyperfluorescence on FITC-dextran whole-mounts. Histology and immunohistochemistry were performed as described previously. Results: VEGF expression in control and treated eyes was confirmed by immunohistochemistry and histological sections indicated recovery of retinal morphology and CNV reduction in treated eyes. In the animals injected by IP with AG013764 or AG013711 the mean CNV level was reduced by 25 to 33% compared to control, but this effect did not achieve statistical significance. Intravitreal injections of AG013764 or AG013711 reduced the level of CNV by approximately 60% compared to control (p< 0.005 or p< 0.05, respectively). Conclusions: These data show that two RTK inhibitors, AG013764 or AG013711, delivered intravitreally, significantly reduce blood vessel proliferation in this AAV-VEGF165 model of CNV.

目的：老年性黄斑变性（AMD）是60岁以上人群致盲的主要原因。在AMD的湿性形式中，靶向生长因子信号传导途径如VEGF的化合物已经成为治疗干预的主要焦点。 在先前开发的大鼠CNV模型中，我们利用两种受体酪氨酸激酶抑制剂（RTKi）阻断CNV建立后的VEGFR-1、VEGFR-2和PDGFR信号传导。 方法：将AAV-VEGF 165注射到出生后15-17天的大鼠视网膜下腔。六周后，在两周的时间内腹膜内（IP，每天两次）或玻璃体内（每五天）注射RTK抑制剂AG 013764或AG 013711的悬浮液。处死动物后，制备RPE-脉络膜-巩膜的FITC-葡聚糖全载片。使用Neurolucida定量CNV面积，以测量FITC-葡聚糖全封片上的高荧光。如前所述进行组织学和免疫组织化学。 结果如下：通过免疫组织化学和组织学切片证实了对照和治疗眼中的VEGF表达，表明治疗眼的视网膜形态恢复和CNV减少。在IP注射AG 013764或AG 013711的动物中，与对照相比，平均CNV水平降低了25 - 33%，但该效应未达到统计学显著性。 与对照相比，玻璃体内注射AG 013764或AG 013711使CNV水平降低约60%（分别为p< 0.005或p< 0.05）。 结论：这些数据显示，玻璃体内递送的两种RTK抑制剂AG 013764或AG 013711显著降低CNV的该AAV-VEGF 165模型中的血管增殖。