Sulfated Polysaccharide Derivatives for Treatment of Macular Degeneration

用于治疗黄斑变性的硫酸化多糖衍生物

• 批准号: 7745143
• 负责人: BALAMURALI K AMBATI
• 金额: $ 14万
• 依托单位: GLYCOMIRA, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745143
• 关键词: Acids; Adhesions; Advanced Glycosylation End Products; Affect; Age related macular degeneration; Age-Years; Albumins; Alkylation; Alzheimer' s Disease; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apoptosis; Binding; Biochemical; Biological Assay; Blindness; Chemistry; Choroidal Neovascularization; Coagulants; Complement; Complement 3a; Complement Activation; Complement Receptor; Complex; Cyclic GMP; Development; Drug Formulations; Drusen; Environment; Epithelial; Epithelial Cells; Event; Factor XII; Family; Feasibility Studies; Glycolipids; Glycosaminoglycans; Goals; Growth; HMGB1 Protein; Heparin; Human; Hyaluronic Acid; ITGAM gene; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Inorganic Sulfates; Investigational New Drug Application; Lasers; Lead; Leukocyte Elastase; Leukocyte L1 Antigen Complex; Leukocyte-Adhesion Receptors; Leukocytes; Life; Ligands; Lysine; Macrophage-1 Antigen; Macular degeneration; Mediating; Modeling; Molecular Weight; Mus; Nature; Oxidants; Oxygen measurement, partial pressure, arterial; P-Selectin; P-selectin ligand protein; Penetration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Plant Roots; Polysaccharides; Prevention; Proteins; Receptor Inhibition; Retina; Retinal; Retinal Diseases; Retinal Pigments; Rupture; Safety; Structure; Structure of retinal pigment epithelium; Time; Tissues; Toxicology; Ultraviolet Rays; Unspecified or Sulfate Ion Sulfates; Vascular Endothelial Growth Factors; alkyl group; analog; in vitro Assay; in vitro testing; in vivo; laser photocoagulation; lead sulfate; molecular size; mouse model; neutrophil; new growth; novel; oxidized lipid; pre-clinical; public health relevance; receptor; research study; retina blood vessel structure; sulfation

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.

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是美国失明的主要原因，影响了800万50岁以上的美国人。其原因是根源于视网膜的高度氧化环境，同时暴露于紫外线和高氧张力。在一生中，视网膜中的氧化事件导致玻璃疣的积累，氧化脂质和蛋白质的复杂聚集，晚期糖基化终产物（AGEs），活化的补体，甚至阿尔茨海默氏症2肽（A2）。随着时间的推移，玻璃疣的积累和所产生的炎症反应产生视网膜色素上皮（RPE）细胞的凋亡和脆性脉络膜血管的旺盛生长，所述脉络膜血管可以破裂，伴随突然的视力丧失。GlycoMira已经合成了几种部分亲脂性的透明质酸硫酸化衍生物，这些衍生物在纳克/毫升浓度下显示出抗炎活性，包括抑制补体激活、P-选择素和人白细胞弹性蛋白酶（HLE）。这些硫酸化和烷基化的HA衍生物还有效地拮抗晚期糖基化终产物受体（Receptor for Advanced Glycation End-products，CRN）与其许多配体的相互作用，所述配体包括羧甲基赖氨酸白蛋白（CML-BSA）、S100钙颗粒蛋白和高迁移率盒族蛋白-1（HMGB-1）。我们假设这些专利药物可以通过抑制AMD视网膜中的无数促炎和血管生成事件而用作AMD的新疗法。在目标1中，将合成类似物并进行化学表征，以通过改变分子大小、硫酸化和烷基化来探索结构-活性空间。在目标2中，将在体外测试对补体、补体激活、P-选择素和HLE的抑制。在目标3中，我们将评估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）在培养的人视网膜上皮细胞中的表达的可行性。使用体外实验中最具活性的化合物，在目标4中，我们将使用激光光凝模型确定阻断小鼠中VEGF介导的脉络膜新血管形成的可行性。在这项可行性研究之后，GlycoMira将进行II期项目，以利用我们的先导药物的玻璃体内制剂的开发，通过预防其他视网膜疾病模型中的脉络膜新生血管来证明其疗效，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：视网膜相关性黄斑变性（AMD）是美国失明的主要原因，影响了800万50岁以上的美国人。在一生中，易感个体的视网膜中的氧化剂事件导致玻璃疣的积累、氧化脂质和蛋白质的合并、晚期糖基化终产物（AGEs）、活化补体和甚至阿尔茨海默氏2肽，导致炎症反应，其产生视网膜色素上皮细胞的凋亡和脆性脉络膜血管的旺盛的新生长，所述脉络膜血管可以破裂，伴随突然的视力丧失。目前治疗AMD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。我们建议开发硫酸化的，部分亲脂性的透明质酸衍生物作为抗补体，抗血小板，抗炎和抗血管生成治疗这种毁灭性的原因失明的老年美国人。