A New Therapy for Diabetic Macular Edema

糖尿病黄斑水肿的新疗法

• 批准号: 6732454
• 负责人: Jian-Xing Ma
• 金额: $ 36.59万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732454
• 关键词: CHO cells; SDS polyacrylamide gel electrophoresis; angiogenesis inhibitors; binding proteins; cell line; diabetic retinopathy; disease /disorder model; dogs; drug administration routes; drug screening /evaluation; edema; electroretinography; histochemistry /cytochemistry; laboratory rat; nonhuman therapy evaluation; pharmacokinetics; plasminogen; polymerase chain reaction; retina disorder; transfection; vascular endothelial growth factors

DESCRIPTION (provided by applicant): This is a R21/R33 phase-combined proposal aiming to develop a new treatment for diabetic macular edema using peptide angiogenic inhibitors. Vascular leakage is an early feature of diabetic retinopathy and can result in diabetic macular edema. Over-expression of VEGF is a major causative factor leading to vascular leakage in diabetic retinopathy. Currently, there is no satisfactory treatment for macular edema which remains a major cause of vision loss in diabetic patients. Plasminogen kringle 5 (K5) is a potent angiogenic inhibitor. Our recent studies have shown that K5 significantly decreases vascular leakage in the retina in the experimental diabetes, laser-induced choroid neovascularization and oxygen-induced retinopathy rat models. The K5- induced reduction of vascular leakage requires only less than one-tenth of the dose needed for the inhibition of neovascularization. Furthermore, our preliminary data suggest that the K5-induced reduction of vascular leakage may be through blocking hypoxia-induced VEGF over-expression in the retina, primarily in Muller cells. We hypothesize that a sustained ocular delivery of K5 may induce a long-term reduction of vascular leakage in diabetic retina and thus, may have therapeutic effect on cyctoid macular edema (CME) secondary to cataract surgery and diabetic macular edema. In the R21 phase, we propose to first reveal the mechanisms for the K5-induced down-regulation of VEGF expression and identify the receptor or binding protein on the cell surface which mediates the K.5-induced reduction of permeability. As diabetic macular edema is a chronic complication of diabetes and requires a long-term treatment, we propose to develop a KS-polymer pellet to achieve a sustained release of K5. The ocular delivery routes of the K5 pellet will be optimized and the pharmacokinetics will be studied in rats. The long-term effect of the K5 pellet on vascular leakage will be determined in a diabetic rat model. The R21 phase will achieve the following goals: 1),to reveal the mechanism and identify the receptor mediating the K5 action, 2) to develop a sustained delivery system for K5 and 3) to prove the concept that a sustained delivery of K5 can induce a prolonged reduction of vascular leakage, The R21 phase will provide essential tools and information for starting the R33 phase. In the R33 phase, we will study the pharmacokinetics of K5 in ocular tissues and optimize the delivery route in normal dogs, With the optimized delivery route, the efficacy of K5 on reduction of vascular leakage will be confirmed in a dog model of vascular leakage induced by intravitreal injection of IGF-1. The possible toxicity of K5 to the retinal vasculature and retinal structure will be examined in both rats and dogs by histochemistry. The retinal function will be examined by ERG recoding. Although this project does not reach clinical trials, the proposed studies will obtain pre-clinical data such as pharmacokinetics, delivery route, efficacy and toxicity from more than one species, which are essential and useful for starting clinical trials. These studies will contribute to the development of a new treatment for CME and for diabetic macular edema. This new treatment will use natural human peptides and will be less invasive. This new therapy, if successful, can prevent vision loss from macular edema in diabetic patients.

描述（由申请人提供）： 这是R21/R33相结合的建议，旨在使用肽血管生成抑制剂开发新的糖尿病黄斑水肿治疗方法。血管泄漏是糖尿病性视网膜病的早期特征，可导致糖尿病黄斑水肿。 VEGF的过表达是导致糖尿病性视网膜病血管泄漏的主要病因。目前，对于黄斑水肿没有令人满意的治疗方法，这仍然是糖尿病患者视力丧失的主要原因。纤溶酶原5（K5）是一种有效的血管生成抑制剂。我们最近的研究表明，K5显着降低了实验性糖尿病，激光诱导的脉络膜新生血管形成和氧诱导的视网膜病变大鼠模型的视网膜的血管渗漏。 K5诱导的血管泄漏减少仅需要抑制新血管形成所需剂量的十分之一。此外，我们的初步数据表明，K5诱导的血管泄漏的减少可能是通过阻断视网膜中缺氧诱导的VEGF过表达的，主要是在Muller细胞中。我们假设K5的持续眼输送可能会导致糖尿病性视网膜中的血管泄漏长期降低，因此可能会对白内障手术和糖尿病性黄斑水肿继发的Cyctoid黄斑水肿（CME）具有治疗作用。在R21阶段，我们建议首先揭示K5诱导的VEGF表达下调的机制，并在细胞表面上鉴定受体或结合蛋白，从而介导K.5诱导的渗透率降低。由于糖尿病性黄斑水肿是糖尿病的慢性并发症，需要长期治疗，因此我们建议开发KS聚合物颗粒以实现K5的持续释放。将优化K5颗粒的眼部输送路线，并将在大鼠中研究药代动力学。 K5颗粒对血管泄漏的长期影响将在糖尿病大鼠模型中确定。 R21阶段将实现以下目标：1），揭示机制并确定介导K5动作的受体，2）为K5和3）开发持续的输送系统，以证明持续的K5的持续交付可以导致长时间减少血管泄漏的降低，R21阶段将为启动R33阶段提供必要的工具和信息。在R33阶段，我们将研究眼组织中K5的药代动力学并优化正常狗的递送途径，并且随着优化的递送途径，K5在减少血管泄漏的功效将在dog dog的血管渗漏模型中证实，这是由IGF-1造成IGF-1引起的。 K5对视网膜脉管系统和视网膜结构的可能毒性将通过组织化学在大鼠和狗中检查。视网膜功能将通过ERG重新编码检查。尽管该项目未进行临床试验，但拟议的研究将获得临床前数据，例如来自多种物种的药代动力学，输送途径，功效和毒性，这对于开始临床试验至关重要且有用。这些研究将有助于开发针对CME和糖尿病黄斑水肿的新治疗方法。这种新的治疗方法将使用天然的人类肽，并且侵入性较小。如果成功的话，这种新疗法可以防止糖尿病患者中黄斑水肿的视力丧失。