Akiyama Hideo, Kachi Shu, Silva Raquel Lima E, Umeda Naoyasu, Hackett Sean F, McCauley Dilara, McCauley Thomas, Zoltoski Anna, Epstein David M, Campochiaro Peter A
Department of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
J Cell Physiol. 2006 May;207(2):407-12. doi: 10.1002/jcp.20583.
Platelet-derived growth factor-B (PDGF-B) has been implicated in the pathogenesis of proliferative retinopathies and other scarring disorders in the eye. In this study, we sought to test the therapeutic potential of an aptamer that selectively binds PDGF-B, ARC126, and its PEGylated derivative, ARC127. Both ARC126 and ARC127 blocked PDGF-B-induced proliferation of cultured fibroblasts with an IC50 of 4 nM. Pharmacokinetic studies in rabbits showed similar peak vitreous concentrations of approximately 110 microM after intravitreous injection of 1 mg of either ARC126 or ARC127, but the terminal half-life was longer for ARC127 (98 versus 43 h). Efficacy was tested in rho/PDGF-B transgenic mice that express PDGF-B in photoreceptors and develop severe proliferative retinopathy resulting in retinal detachment. Compared to eyes injected with 20 microg of scrambled aptamer in which five of six developed detachments (three total and two partial), eyes injected with ARC126 (no detachment in five of six and one partial detachment), or ARC127 (no detachment in six of six) had significantly fewer retinal detachments. They also showed a significant reduction in epiretinal membrane formation. These data demonstrate that a single intravitreous injection of an aptamer that specifically binds PDGF-B is able to significantly reduce epiretinal membrane formation and retinal detachment in rho/PDGF-B mice. These striking effects in an aggressive model of proliferative retinopathy suggest that ARC126 and ARC127 should be considered for treatment of diseases in which PDGF-B has been implicated, including ischemic retinopathies such as proliferative diabetic retinopathy, proliferative vitreoretinopathy (PVR), and choroidal neovascularization.
血小板衍生生长因子 -B（PDGF -B）与增殖性视网膜病变及眼部其他瘢痕性疾病的发病机制有关。在本研究中，我们试图测试一种能选择性结合PDGF -B的适配体ARC126及其聚乙二醇化衍生物ARC127的治疗潜力。ARC126和ARC127均可阻断PDGF -B诱导的培养成纤维细胞增殖，半数抑制浓度（IC50）为4 nM。家兔的药代动力学研究表明，玻璃体内注射1 mg的ARC126或ARC127后，玻璃体内的峰值浓度相似，约为110 μM，但ARC127的终末半衰期更长（分别为98小时和43小时）。在rho/PDGF -B转基因小鼠中测试了其疗效，该小鼠在光感受器中表达PDGF -B，并发展为严重的增殖性视网膜病变，导致视网膜脱离。与注射20 μg乱序适配体的眼睛相比（六只中有五只发生脱离，三只完全脱离，两只部分脱离），注射ARC126的眼睛（六只中有五只未发生脱离，一只部分脱离）或ARC127的眼睛（六只均未发生脱离）视网膜脱离明显减少。它们还显示视网膜前膜形成显著减少。这些数据表明，单次玻璃体内注射特异性结合PDGF -B的适配体能够显著减少rho/PDGF -B小鼠的视网膜前膜形成和视网膜脱离。在增殖性视网膜病变的侵袭性模型中的这些显著效果表明，对于PDGF -B参与其中的疾病，包括缺血性视网膜病变，如增殖性糖尿病视网膜病变、增殖性玻璃体视网膜病变（PVR）和脉络膜新生血管形成，应考虑使用ARC126和ARC127进行治疗。
