Ma Jie, Sun Yu, López Francisco J, Adamson Peter, Kurali Edit, Lashkari Kameran
Schepens Eye Research Institute Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States.
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States.
Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):3138-44. doi: 10.1167/iovs.15-18795.
Choroidal neovascularization (CNV) is a major cause of visual loss with age-related macular degeneration (AMD). We evaluated whether blockade of phosphatidyl-inositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR), by impairing VEGF-A and other growth factor receptors like platelet-derived growth factor (PDGF), would reduce laser-induced CNV in mice.
Choroidal neovascularization lesions were induced in C57BL/6 mice. Two groups of mice received oral GSK2126458 (3 mg/kg) or vehicle for 14 days following laser, whereas three groups were treated with GSK2126458 (6 μg/eye), aflibercept (2 μL/eye), or vehicle intravitreally on days 0 and 7 after laser. Vascular leakage was measured by fluorescein angiography (FA) on day 14. Choroidal neovascularization membranes were evaluated on choroidal flat mounts following FITC-dextran perfusion, as well as ED1 and isolectin B4 (IB4) immunohistochemistry.
Oral and intravitreal (IVT) GSK2126458 reduced leakage and area of CNV lesions. Greater probability of leaking lesions (∼60%; P < 0.05) was observed in both vehicle groups. Fluorescein isothiocyanate-dextran-labeled total CNV burden area (total lesion area/eye) was reduced ∼67% (P < 0.05) and 35% (P = 0.0528) after oral and IVT GSK2126458 administration. GSK2126458 treatment reduced lesion size by ∼80% (P < 0.05) and 50% (P < 0.05) for oral and IVT control groups. Aflibercept did not alter lesion size (∼27% reduction).
Phosphatidyl-inositol-3-kinase/mTOR is involved in laser-induced CNV angiogenic processes. GSK2126458 effectively reduces CNV size and leakage. Choroidal neovascularization size following IVT GSK2126458 was smaller than after oral administration. Therefore, inhibition of PI3K/mTOR pathways may be more effective due to blockade of action of multiple growth factors.
脉络膜新生血管（CNV）是年龄相关性黄斑变性（AMD）导致视力丧失的主要原因。我们评估了通过损害血管内皮生长因子A（VEGF-A）和其他生长因子受体（如血小板衍生生长因子（PDGF））来阻断磷脂酰肌醇-3激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR）是否会减少小鼠激光诱导的CNV。
在C57BL/6小鼠中诱导脉络膜新生血管病变。两组小鼠在激光照射后口服GSK2126458（3mg/kg）或赋形剂，持续14天，而三组在激光照射后的第0天和第7天接受玻璃体内注射GSK2126458（6μg/眼）、阿柏西普（2μL/眼）或赋形剂。在第14天通过荧光素血管造影（FA）测量血管渗漏。在异硫氰酸荧光素-葡聚糖灌注后，对脉络膜扁平标本进行评估，以观察脉络膜新生血管膜，同时进行ED1和异凝集素B4（IB4）免疫组织化学分析。
口服和玻璃体内注射（IVT）GSK2126458可减少CNV病变的渗漏和面积。在两个赋形剂组中均观察到渗漏病变的可能性更高（约60%；P<0.05）。口服和玻璃体内注射GSK2126458后，异硫氰酸荧光素-葡聚糖标记的总CNV负荷面积（每只眼睛的总病变面积）分别减少了约67%（P<0.05）和35%（P=0.0528）。对于口服和玻璃体内注射对照组，GSK2126458治疗使病变大小分别减少了约80%（P<0.05）和50%（P<0.05）。阿柏西普未改变病变大小（减少约27%）。
磷脂酰肌醇-3激酶/哺乳动物雷帕霉素靶蛋白参与激光诱导的CNV血管生成过程。GSK2126458可有效减少CNV大小和渗漏。玻璃体内注射GSK2126458后脉络膜新生血管的大小小于口服给药后。因此，由于阻断了多种生长因子的作用，抑制PI3K/mTOR途径可能更有效。
