Miki Katsuaki, Miki Akiko, Matsuoka Masato, Muramatsu Daisuke, Hackett Sean F, Campochiaro Peter A
Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277, USA.
Ophthalmology. 2009 Sep;116(9):1748-54. doi: 10.1016/j.ophtha.2009.05.020. Epub 2009 Jul 29.
This study compared the effects of intraocular injections of ranibizumab (RBZ) and bevacizumab (BVZ) in transgenic mouse models in which human vascular endothelial growth factor (VEGF) causes subretinal neovascularization (NV) or exudative retinal detachment.
Randomized trials in animal models.
Transgenic mice in which the rhodopsin promoter drives expression of human VEGF in photoreceptors (rho/VEGF mice) and double transgenic mice with doxycycline-inducible expression of human VEGF in photoreceptors (Tet/opsin/VEGF mice).
Rho/VEGF mice received intraocular injections of RBZ, BVZ, or vehicle, and after various time periods the area of subretinal NV was measured. Tet/opsin/VEGF mice were given an intraocular injection of RBZ, BVZ, or vehicle, and after 5 days of doxycycline treatment the presence or absence of retinal detachment was determined.
Area of subretinal NV per retina in rho/VEGF mice and the occurrence of retinal detachment in Tet/opsin/VEGF mice.
In rho/VEGF mice, intraocular injections of RBZ or BVZ strongly suppressed subretinal NV, but the duration of effect was greater for BVZ. Three injections of 10 microg of BVZ over the course of 2 weeks not only suppressed subretinal NV in the injected eye but also caused significant suppression in the fellow eye, indicating a systemic effect. In doxycycline-treated Tet/opsin/VEGF mice, intraocular injection of 10 microg of BVZ significantly reduced the incidence of exudative retinal detachment compared with injection of 10 microg of RBZ. Injection of 25 microg of BVZ reduced the incidence of retinal detachment in both eyes.
Intraocular injections of RBZ and BVZ had similar efficacy in rho/VEGF mice, but the duration of effect was greater for BVZ. In Tet/opsin/VEGF mice, in which expression levels of human VEGF are very high and the phenotype is severe, BVZ showed greater efficacy than RBZ. In both models, higher doses or repeated injections of BVZ, but not RBZ, resulted in a systemic effect. These data suggest that BVZ is not inferior to RBZ for treatment of subretinal NV in mice and is superior in a severe model. The systemic effects of BVZ after intraocular injection deserve further study and consideration of their potential consequences.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
本研究比较了玻璃体内注射雷珠单抗（RBZ）和贝伐单抗（BVZ）在人血管内皮生长因子（VEGF）导致视网膜下新生血管形成（NV）或渗出性视网膜脱离的转基因小鼠模型中的效果。
动物模型随机试验。
视紫红质启动子驱动人VEGF在光感受器中表达的转基因小鼠（rho/VEGF小鼠）以及强力霉素诱导人VEGF在光感受器中表达的双转基因小鼠（Tet/视蛋白/VEGF小鼠）。
给rho/VEGF小鼠玻璃体内注射RBZ、BVZ或赋形剂，在不同时间段后测量视网膜下NV的面积。给Tet/视蛋白/VEGF小鼠玻璃体内注射RBZ、BVZ或赋形剂，并在强力霉素治疗5天后确定是否存在视网膜脱离。
rho/VEGF小鼠每个视网膜的视网膜下NV面积以及Tet/视蛋白/VEGF小鼠视网膜脱离的发生情况。
在rho/VEGF小鼠中，玻璃体内注射RBZ或BVZ可强烈抑制视网膜下NV，但BVZ的作用持续时间更长。在2周内分三次注射10微克BVZ，不仅抑制了注射眼的视网膜下NV，还导致对侧眼显著抑制，表明有全身效应。在强力霉素治疗的Tet/视蛋白/VEGF小鼠中，与注射10微克RBZ相比，玻璃体内注射10微克BVZ可显著降低渗出性视网膜脱离的发生率。注射25微克BVZ可降低双眼视网膜脱离的发生率。
在rho/VEGF小鼠中，玻璃体内注射RBZ和BVZ具有相似的疗效，但BVZ的作用持续时间更长。在人VEGF表达水平非常高且表型严重的Tet/视蛋白/VEGF小鼠中，BVZ显示出比RBZ更高的疗效。在两种模型中，更高剂量或重复注射BVZ（而非RBZ）会产生全身效应。这些数据表明，BVZ在治疗小鼠视网膜下NV方面并不逊于RBZ，且在严重模型中更具优势。玻璃体内注射BVZ后的全身效应值得进一步研究并考虑其潜在后果。
专有或商业披露信息可在参考文献之后找到。
