Peptide Eyedrops for Treatment of Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变是糖尿病的常见并发症，也是美国和世界上导致失明的主要原因。糖尿病黄斑水肿(DME)和视网膜新生血管是糖尿病视网膜病变中导致视力丧失的两种主要病理改变。视网膜血管高通透性或血管渗漏是DME的主要原因。视网膜中血管内皮生长因子(VEGF)的过度表达在BRB的破坏中起着重要作用。目前，DME尚无有效的非侵入性治疗方法。需要一种新的、非侵入性和经济有效的治疗方法来治疗DME。 纤溶酶原kringle5(K5)是纤溶酶原的80个氨基酸组成的片段，具有很强的抗血管生成活性，如抑制血管内皮细胞的增殖和迁移，这是血管生成中的一个重要过程。我们以前的研究已经证明，K5在三个独立的视网膜病变动物模型上，一次眼内或眼周注射小剂量的K5，可以有效地阻断视网膜中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使用K5滴眼液来实现。这些结果表明，给予这种血管生成抑制物对DME有治疗作用。我们推测，持续局部应用K5滴眼液可能会成为治疗DME的一种有效的非侵入性治疗方法。 该一期工程的目的是证明K5滴眼液对链脲佐菌素诱导的糖尿病大鼠视网膜血管渗漏有长期治疗作用。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滴眼液在糖尿病大鼠体内的药代动力学和分布。然后，我们将确定持续给予K5滴眼液是否可以持续减少糖尿病大鼠模型的视网膜血管渗漏。 血管通透性测定采用伊文思蓝-白蛋白和荧光素-白蛋白渗漏法。第一阶段项目不仅将解决使用K5眼药水治疗二甲基醚的可行性，而且还将产生必要的数据，并为在第二阶段研究中开发适销对路的产品奠定坚实的基础。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的方法。

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.