MASP-2 Therapy for Macular Degeneration

MASP-2 治疗黄斑变性

基本信息

批准号：
7218775
负责人：
CLARK E TEDFORD
金额：
$ 14.21万
依托单位：
OMEROS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7218775
关键词：
A Mouse Accounting Affect Age Age related macular degeneration Angiogenic Factor Animal Model Animals Applications Grants Automobile Driving Blindness Cells Choroid Choroidal Neovascularization Cicatrix Class Clinical Complement Complement 2 Complement 3a Complement 5a Complement Activation Complement Inactivators Complex Country Deposition Development Diabetic Retinopathy Disease Elderly Emotional End Point Enzyme-Linked Immunosorbent Assay Evaluation Exudative age-related macular degeneration Flow Cytometry Glaucoma Goals Grant Host Defense Mechanism Human Immune Impairment Individual Inflammation Inflammatory Inflammatory Response Injury Investigation Kentucky Knockout Mice Laboratories Laser Scanning Confocal Microscopy Laser injury Lasers Lectin Left Licensing Macular degeneration Measures Mediating Medicine Modeling Monoclonal Antibodies Mus National Eye Institute Neutrophil Infiltration Nonexudative age-related macular degeneration Outcome Pathogenesis Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Plasma Play Population Predisposition Program Development Proteins Reading Regulation Reperfusion Injury Research Research Personnel Risk Role Serine Protease Side Small Business Funding Mechanisms Small Business Innovation Research Grant Strategic Planning Structure of retinal pigment epithelium Subgroup System Testing Therapeutic Agents Therapeutic Intervention Therapeutic Uses Thinking Tissue Donors Tissues United States United States Food and Drug Administration Universities Vascular Endothelial Growth Factors Vision base college complement pathway concept drug development human MASP2 protein human disease inhibitor/antagonist interest macrophage macula mannose-binding protein-associated serine proteases mouse Masp2 protein neovascular novel novel therapeutics ophthalmic drug pathogen pegaptanib size socioeconomics therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The overall goal is to develop monoclonal antibody-based compounds capable of blocking human MASP-2 function as potential therapeutic agents for the treatment of age-related macular degeneration (AMD). MASP-2 is a plasma serine protease uniquely required for complement activation via the lectin pathway and may be an attractive target for the development of novel therapeutics for inflammatory disorders. The complement system is an important host defense mechanism; however, excessive or uncontrolled complement activation can trigger an intense inflammatory response that is thought to significantly contribute to undesired tissue damage in many disease states. Recent results implicate a central role for complement activation in the pathogenesis of AMD, and especially of choroidal neovascularization (CNV) the most serious form of AMD. Three pathways have been described for complement activation: the classical, alternative and lectin pathways. To treat AMD it would be desirable to develop pathway-specific inhibitors which would target only the complement pathway causing the particular pathology without completely shutting down the immune defense capabilities of complement. Immunohistological studies of human donor tissues indicate that the classical pathway does not play a major role in triggering complement activation in AMD. Recent studies indicate that the lectin pathway may have a critical role in triggering complement activation in many tissue injury settings, especially when there is no evident role for the classical pathway in the disease pathogenesis. A mouse genetically-deficient in the MASP-2 protein has been developed. The availability of the MASP-2 (-/-) mouse and the genetically-matched MASP-2 (+/+) mouse provides a powerful research tool to directly evaluate the pathogenic role of MASP-2 and the lectin-dependent complement system in murine models of CNV and AMD. The specific objectives in this SBIR grant application are to compare and contrast the results obtained when MASP-2 (-/-) and MASP-2 (+/+) mice are evaluated in the course of laser-induced CNV, an accelerated model of neovascular AMD. A successful outcome in the Phase I studies would indicate that MASP-2 is an attractive therapeutic target for the treatment of the CNV (wet) form of AMD. A Phase II application would focus on the development of blocking monoclonal antibody-based compounds specific for MASP-2 as potential therapeutic agents for AMD. Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 and it is estimated that 1.75 million individuals suffer from this disease in the United States, with another 7 million "at risk". In this SBIR grant, studies will evaluate a potential new target called MASP-2 for treatment of AMD. Studies will be conducted in mice deficient in MASP-2 to determine their susceptibility to AMD and would provide support for this as a novel target in AMD medication development.

描述（由申请人提供）：总体目标是开发能够阻断人 MASP-2 功能的基于单克隆抗体的化合物，作为治疗年龄相关性黄斑变性 (AMD) 的潜在治疗剂。 MASP-2 是一种血浆丝氨酸蛋白酶，是通过凝集素途径激活补体所必需的，并且可能是开发炎症性疾病新型疗法的一个有吸引力的靶标。补体系统是重要的宿主防御机制；然而，过度或不受控制的补体激活会引发强烈的炎症反应，这被认为会在许多疾病状态下显着导致不良的组织损伤。最近的结果表明补体激活在 AMD 的发病机制中发挥着核心作用，尤其是脉络膜新生血管 (CNV)（AMD 最严重的形式）的发病机制。补体激活的三种途径已被描述：经典途径、替代途径和凝集素途径。为了治疗 AMD，需要开发途径特异性抑制剂，该抑制剂仅针对引起特定病理的补体途径，而不完全关闭补体的免疫防御能力。对人类供体组织的免疫组织学研究表明，经典途径在 AMD 中触发补体激活中并不起主要作用。最近的研究表明，凝集素途径可能在许多组织损伤情况下触发补体激活中发挥关键作用，特别是当经典途径在疾病发病机制中没有明显作用时。一种 MASP-2 蛋白基因缺陷的小鼠已被开发出来。 MASP-2 (-/-) 小鼠和基因匹配的 MASP-2 (+/+) 小鼠的出现为直接评估 MASP-2 和凝集素依赖性补体系统的致病作用提供了强大的研究工具。 CNV 和 AMD 的小鼠模型。本次 SBIR 拨款申请的具体目标是比较和对比在激光诱导 CNV（一种加速模型）过程中评估 MASP-2 (-/-) 和 MASP-2 (+/+) 小鼠时获得的结果。新生血管性AMD。 I 期研究的成功结果表明，MASP-2 是治疗 CNV（湿性）AMD 的一个有吸引力的治疗靶点。 II 期申请将重点开发针对 MASP-2 的阻断性单克隆抗体化合物，作为 AMD 的潜在治疗剂。年龄相关性黄斑变性 (AMD) 是 55 岁以后失明的主要原因，据估计，美国有 175 万人患有这种疾病，另有 700 万人处于“危险之中”。在这笔 SBIR 拨款中，研究将评估一种名为 MASP-2 的潜在新靶点，用于治疗 AMD。将对 MASP-2 缺陷的小鼠进行研究，以确定它们对 AMD 的易感性，并为其作为 AMD 药物开发的新靶点提供支持。