Peptide Eyedrops for Treatment of Diabetic Retinopathy

用于治疗糖尿病视网膜病变的肽滴眼液

• 批准号: 6991773
• 负责人: KANGMO LU
• 金额: $ 13.38万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6991773
• 关键词: diabetic retinopathy; disease /disorder model; eye agent; eye disorder chemotherapy; laboratory rat; nonhuman therapy evaluation; peptides; pharmacokinetics; plasminogen; retina; therapy design /development; topical drug application; vascular endothelium permeability

DESCRIPTION (provided by applicant): Diabetic retinopathy is a common complication of diabetes and a leading cause of blindness in the US and the world. Diabetic macular edema (DME) and retinal neovascularization are the two major pathological alternations leading to the vision loss in diabetic retinopathy. The retinal vascular hyper-permeability or vascular leakage is primarily responsible for DME. Over-expression of vascular endothelial growth factor (VEGF) in the retina plays a crucial role in the BRB breakdown. Currently, there is no effective and noninvasive treatment for DME. A new, non-invasive and cost-effective treatment for DME is needed. It has been found that plasminogen kringle 5 (K5), an 80-amino acid fragment of plasminogen, has the potent anti-angiogenic activity, such as inhibiting the endothelial cell proliferation and migration, which are an important process in angiogenesis. Our previous studies have demonstrated that K5 blocks the VEGF overproduction in the retina and effectively reduces retinal vascular leakage in three independent retinopathy animal models after a single intra-ocular or peri-ocular injection of a low dose. Moreover, the effect of K5 on vascular permeability can be achieved via topical application of K5 eyedrops. These results suggest that administration of this angiogenic inhibitor should have therapeutic effect on DME. We hypothesize that the continuous topical application of K5 eyedrops may become an effective and non-invasive therapy for DME. The objective of this Phase I project is to prove the concept that the K5 eyedrop administration can have long-term therapeutic effect on vascular leakage in the retina of STZ-induced diabetic rats. To obtain the effective concentration of K5 eyedrops for blocking retinal vascular leakage in diabetic rats, we will investigate the pharmacokinetics and distribution of K5 after the administration of K5 eyedrops. Then, we will determine if continuous administration of the K5 eyedrop can result in sustained reduction of retinal vascular leakage in the diabetic rat model. The vascular permeability will be measured by the Evans blue-albumin and fluorescein-albumin leakage methods. The Phase I project will not only address the feasibility to use K5 eyedrops for the treatment of DME, but also generate essential data and lay a solid ground for the development of a marketable product in the Phase II studies. Our long-term goal is to develop a novel, noninvasive, effective therapy for DME.

描述（由申请人提供）：糖尿病视网膜病变是糖尿病的常见并发症，也是美国和世界上致盲的主要原因。糖尿病性黄斑水肿（DME）和视网膜新生血管是导致糖尿病性视网膜病变视力下降的两种主要病理改变。视网膜血管通透性过高或血管渗漏是导致DME的主要原因。血管内皮生长因子（VEGF）在视网膜中的过度表达在BRB破裂中起着至关重要的作用。目前，对于DME没有有效的非侵入性治疗。一种新的，非侵入性和成本效益的治疗DME是必要的。 纤溶酶原kringle 5（K5）是纤溶酶原的一个80个氨基酸的片段，具有抑制血管生成的作用，如抑制内皮细胞的增殖和迁移，这是血管生成的重要过程。我们先前的研究已经证明，在三种独立的视网膜病变动物模型中，在单次眼内或眼周注射低剂量后，K5阻断视网膜中VEGF的过度产生，并有效地减少视网膜血管渗漏。此外，K5对血管通透性的影响可以通过局部应用K5滴眼剂来实现。这些结果表明，这种血管生成抑制剂的管理应该有DME的治疗效果。我们推测持续局部应用K5滴眼液可能成为DME的有效和非侵入性治疗。 该I期项目的目的是证明K5滴眼液给药对STZ诱导的糖尿病大鼠视网膜血管渗漏具有长期治疗效果的概念。为了获得K5滴眼液阻断糖尿病大鼠视网膜血管渗漏的有效浓度，我们将研究K5滴眼液给药后K5的药代动力学和分布。然后，我们将确定在糖尿病大鼠模型中连续施用K5滴眼液是否可以导致视网膜血管渗漏的持续减少。 将通过伊文思蓝-白蛋白和荧光素-白蛋白渗漏法测量血管通透性。第一阶段项目不仅将研究使用K5眼药水治疗DME的可行性，还将为第二阶段研究中开发可销售的产品提供必要的数据并奠定坚实的基础。我们的长期目标是开发一种新的，非侵入性的，有效的治疗DME。