Novel Linomide Analog for Treatment of Diabetic Retinopathy

描述（由申请人提供）：项目摘要/摘要：糖尿病视网膜病变（DR）是糖尿病的常见并发症，也是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（NV）是导致糖尿病性视网膜病变视力下降的两大病理改变。血管生成和炎症在DR的发病机制中起着至关重要的作用。炎症细胞浸润到糖尿病视网膜，白细胞停滞和分泌促血管生成细胞因子是导致毛细血管无灌注，局部缺血和随后的视网膜血管通透性过高和内皮细胞增殖的原因。目前，对于视网膜NV和DME没有无创、经济和有效的治疗方法。Linomide是一种新型的水溶性有机分子，具有抗炎和抗血管生成活性。用于预防自身免疫性疾病和抑制肿瘤生长。Linomide在DR治疗中的抗炎和抗血管生成作用尚未报道。最近，我们的合作者通过用H取代Linomide中的N-甲基，合成了一种新型Linomide类似物（Linomide 5）。Linomide 5在大鼠中表现出显著更有效的特异性抗增殖活性和抑制实验性脉络膜新生血管（CNV）。我们假设这种新型的Linomide类似物在DME和视网膜NV的治疗中具有治疗潜力。我们的目标是开发更有效、特异的抗炎和抗血管生成药物，以预防和阻止视网膜血管渗漏和NV。I期项目将确定这种新型化合物对DR动物模型中炎症因子表达和视网膜血管渗漏的功效。我们将确定玻璃体内施用Linomide是否可以减少视网膜白细胞淤滞和促炎因子，如肿瘤坏死因子-α（TNF-α），细胞间粘附分子-1（ICAM-1），单核细胞趋化蛋白-1（MCP-1）的表达。我们还将在OIR大鼠模型中研究新型Linomide类似物对视网膜血管内皮生长因子（VEGF）表达和血管通透性的影响。这些研究有可能鉴定出具有治疗视网膜NV和DME的治疗潜力的新型化合物。在未来的II期研究中，我们将专注于毒性和药代动力学研究，以开发新的抗血管生成和抗炎药物。因此，如果获得资助，该项目有可能产生用于治疗重大致盲性疾病的可销售产品。由于视网膜NV和DME影响大量人群，并且没有有效的药物可用，这些新的抗血管生成药物应该具有巨大的商业潜力。项目叙述：血管生成和炎症在糖尿病视网膜病变的发病机制中起关键作用，糖尿病视网膜病变是世界上主要的致盲原因。我们将研究一种新化合物（Linomide 5）对糖尿病动物模型中视网膜炎症和血管生成的影响。本课题的目的是研制一种特异有效的药物，预防和治疗糖尿病患者的视网膜并发症。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness in the world. Diabetic macular edema (DME) and retinal neovascularization (NV) are the 2 major pathological alternations leading to the vision loss in diabetic retinopathy. Angiogenesis and inflammation play a crucial role in the pathogenesis of DR. Inflammatory cells infiltrated into diabetic retina, leukostasis and secreted pro-angiogenetic cytokines are responsible for capillary non-perfusion, local ischemia and subsequent retinal vascular hyper-permeability and endothelial cell proliferation. Currently, there is no non-invasive, economic and effective therapy available for retinal NV and DME. Linomide, a novel water-soluble organic molecule, has been shown to have both anti-inflammatory and anti-angiogenic activities. It is used for preventing autoimmune diseases and inhibiting tumor growth. The anti-inflammatory and anti-angiogenic effects of Linomide has not been reported in the treatment of DR. Recently, our collaborator has synthesized a novel Linomide analog (Linomide 5) by replacing the N-methyl groups in Linomide with H. Linomide 5 has exhibited significantly more potent specific anti-proliferative activity and suppressed experimental choroidal neovascularization (CNV) in rats. We hypothesize that this novel Linomide analog has therapeutic potential in the treatment of DME and retinal NV. Our objective is to develop more potent, specific anti-inflammatory and anti-angiogenic drugs, which can prevent and arrest the retinal vascular leakage and NV. The Phase I project will determine the efficacy of this novel compound on the expression of inflammatory factors and retinal vascular leakage in animal models of DR. We will determine whether the intravitreal administration of Linomide can reduce retinal leukostasis and pro-inflammatory factors, such as tumor necrosis factor-alpha (TNF-a), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1) in STZ- diabetic rats. We will also study the effect of novel Linomide analog on retinal vascular endothelial growth factor (VEGF) expression and vascular permeability in an OIR rat model. These studies have potential to identify a novel compound with therapeutic potential for the treatment of retinal NV and DME. In Future Phase II studies, we will focus on toxcicty and pharmacokinetic studies to develop new anti-angiogenic and anti-inflammatory drugs. Therefore, this project, if funded, has potential to generate a marketable product for the treatment of a major blinding disease. As retinal NV and DME affect a large population, and there is no effective drug available, these new anti-angiogenic drugs should have great commercial potential. Project Narrative: Angiogenesis and inflammation play a key role in the pathogenesis of diabetic retinopathy, which is a leading cause of blindness in the world. We will study the effect of a new compound (Linomide5) on retinal inflammation and angiogenesis in diabetic animal models. The purpose of this project is to develop a specific and effective drug, which can prevent and treat the retinal complications in diabetic patients.