Sulfated Polysaccharide Derivatives for Treatment of Macular Degeneration

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是美国失明的主要原因，影响了800万50岁以上的美国人。其原因是视网膜的高度氧化环境，同时暴露在紫外线和高氧张力下。在一生中，视网膜中的氧化事件导致drusen的积累，氧化脂质和蛋白质的复杂聚集，晚期糖基化终产物（AGEs），活化补体甚至阿尔茨海默病2肽（A2）。随着时间的推移，酒精的积累和由此产生的炎症反应导致视网膜色素上皮细胞（RPE）的凋亡和脆性脉络膜血管的旺盛生长，这些血管可能破裂，并突然丧失视力。GlycoMira已经合成了几种部分亲脂、硫酸化的透明质酸衍生物，这些衍生物在纳克/毫升浓度下具有抗炎活性，包括抑制补体激活、p -选择素和人类白细胞弹性酶（HLE）。这些硫酸化和烷基化的透明质酸衍生物还能有效地拮抗晚期糖基化终产物受体（RAGE）与其许多配体的相互作用，包括羧基甲基赖氨酸白蛋白（CML-BSA）、S100钙颗粒蛋白和高迁移率盒基蛋白-1 （HMGB-1）。我们假设这些专有药物可以通过抑制AMD视网膜中无数的促炎和血管生成事件来作为一种新的治疗AMD的药物。在Aim 1中，将合成类似物并对其进行化学表征，通过改变分子大小、磺化和烷基化来探索结构-活性空间。在Aim 2中，我们将在体外测试补体抑制、RAGE激活、p -选择素和HLE。在Aim 3中，我们将评估在培养的人视网膜上皮细胞中使用这些化合物拮抗AGE/ rage介导的细胞凋亡和血管内皮生长因子（VEGF）表达的可行性。使用体外实验中最活跃的化合物，在Aim 4中，我们将使用激光光凝模型确定阻断vegf介导的小鼠脉络膜新生血管的可行性。在这项可行性研究之后，GlycoMira将继续进行II期项目，以利用我们的先导药物的玻璃体内配方的开发，证明其在其他视网膜疾病模型中预防脉络膜新生血管的功效，并完成研究性新药申请（IND）所需的制造和毒理学研究。公共卫生相关性：老年性黄斑变性（AMD）是美国失明的主要原因，影响了800万50岁以上的美国人。在一生中，易感个体视网膜中的氧化事件导致drusen的积累，氧化脂质和蛋白质的合并，晚期糖基化终产物（AGEs），活化补体甚至阿尔茨海默氏2肽，导致炎症反应，导致视网膜色素上皮细胞凋亡和脆性脉络膜血管的旺盛新生，可能破裂，突然丧失视力。目前治疗黄斑变性的方法是玻璃体内注射抗血管内皮生长因子（VEGF）的抗体，这种方法既昂贵又不完善。我们建议开发磺化的、部分亲脂的氢月果酸衍生物，作为抗补体、抗rage、抗炎和抗血管生成的治疗方法，用于治疗美国老年人失明的这种毁灭性原因。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a leading cause of blindness in the U.S., affecting 8 million Americans over fifty years of age. Its cause is rooted in the highly oxidizing environment of the retina, which is simultaneously exposed to UV light and high oxygen tensions. Over a lifetime, oxidant events in the retina lead to accumulation of drusen, a complex aggregation of oxidized lipids and proteins, Advanced Glycation End-products (AGEs), activated complement and even Alzheimer's 2 peptide (A2). With time, drusen accumulation and the resulting inflammatory response produces apoptosis of retinal pigment epithelial (RPE) cells and exuberant growth of brittle choroidal vessels which can rupture, with abrupt loss of vision. GlycoMira has synthesized several partially lipophilic, sulfated derivatives of hyaluronic acid that show anti-inflammatory activities at nanogram/ml concentrations, including inhibition of complement activation, P-selectin and human leukocyte elastase (HLE). These sulfated and alkylated HA derivatives also potently antagonize the interaction of the Receptor for Advanced Glycation End-products (RAGE) with its many ligands, including carboxy-methyl lysine albumin (CML-BSA), S100 calgranulins, and high mobility box group protein-1 (HMGB-1). We hypothesize that these proprietary agents can be used as a novel therapy for AMD by inhibiting the myriad pro-inflammatory and angiogenic events in the AMD retina. In Aim 1, analogs will be synthesized and chemically characterized to explore structure-activity space by varying molecular size, sulfation and alkylation. In Aim 2, the inhibition of complement, RAGE activation, P-selectin and HLE will be tested in vitro. In Aim 3, we will evaluate the feasibility of using these compounds to antagonize AGE/RAGE-mediated apoptosis and expression of vascular endothelial growth factor (VEGF) in cultured human retinal epithelial cells. Using the most active compound from in vitro experiments, in Aim 4 we will the determine feasilibity of blocking VEGF-mediated choroidal neovascularization in mice using a laser photocoagulation model. Following this feasibility study, GlycoMira would pursue a Phase II project to leverage the development of an intra-vitreal formulation of our lead drug, demonstrate its efficacy by prevention of choroidal neovascularization in other models of retinal diseases, and complete the manufacturing and toxicology studies required for an investigational new drug application (IND). PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S., affecting 8 million Americans over fifty years of age. Over a life-time, oxidant events in the retina of susceptible individuals lead to accumulation of drusen, an amalgamation of oxidized lipids and proteins, Advanced Glycation EndproductS (AGEs), activated complement and even Alzheimer's 2 peptide, resulting in an inflammatory response that produces apoptosis of retinal pigment epithelial cells and exuberant new growth of brittle choroidal vessels which can rupture, with abrupt loss of vision. The current therapy for AMD, intravitreal injection of antibodies against vascular endothelial growth factor (VEGF), is expensive and imperfect. We propose to develop sulfated, partially lipophilic hylauronic acid derivatives as an anti-complement, anti-RAGE, anti-inflammatory and anti-angiogenic therapy for this devastating cause of blindness in older Americans.