Intraocular injection of an aptamer that binds PDGF-B: A potential treatment for proliferative retinopathies
Intraocular injection of an aptamer that binds PDGF-B: A potential treatment for proliferative retinopathies
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DOI：
10.1002/jcp.20583
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发表时间：
2006-05-01
影响因子：
5.6
通讯作者：
Campochiaro, PA
中科院分区：
文献类型：
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作者：
Akiyama, H;Kachi, S;Campochiaro, PA
血小板源性生长因子-B（PDGF-B）与增生性视网膜病和其他眼部瘢痕形成疾病的发病机制有关。在这项研究中，我们试图测试选择性结合PDGF-B的适体ARC 126及其PEG化衍生物ARC 127的治疗潜力。ARC 126和ARC 127均以4 nM的IC 50阻断PDGF-B诱导的培养成纤维细胞增殖。兔的药代动力学研究显示，玻璃体内注射1 mg ARC 126或ARC 127后，玻璃体浓度峰值相似，约为110 μ M，但ARC 127的终末半衰期较长（98小时对43小时）。在rho/PDGF-B转基因小鼠中测试功效，所述小鼠在光感受器中表达PDGF-B并且发展导致视网膜脱离的严重增殖性视网膜病变。与注射20 μ g乱序适体的眼睛相比，其中6只眼睛中有5只发生视网膜脱离（3只全部发生，2只部分发生），注射ARC 126（6只眼睛中有5只没有脱离，1只部分脱离）或ARC 127（6只眼睛中有6只没有脱离）的眼睛具有显著更少的视网膜脱离。他们还显示出视网膜前膜形成的显著减少。这些数据表明，特异性结合PDGF-B的适体的单次玻璃体内注射能够显著减少rho/PDGF-B小鼠中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作用表明，ARC 126和ARC 127应被考虑用于治疗与PDGF-B有关的疾病，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。
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 mu M 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 mu g 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.