MASP-2 Therapy for Macular Degeneration

MASP-2 治疗黄斑变性

• 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
• 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

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，作为用于治疗年龄相关性黄斑变性（AMD）的潜在治疗剂。MASP-2是通过凝集素途径进行补体活化所独特需要的血浆丝氨酸蛋白酶，并且可能是开发用于炎性病症的新型治疗剂的有吸引力的靶标。补体系统是一种重要的宿主防御机制;然而，过度或不受控制的补体激活可引发强烈的炎症反应，其被认为在许多疾病状态中显著促成不期望的组织损伤。最近的研究结果表明，补体激活在AMD的发病机制中起着重要作用，尤其是在最严重的AMD形式--脉络膜新生血管（CNV）的发病机制中。已经描述了补体激活的三种途径：经典途径、替代途径和凝集素途径。为了治疗AMD，期望开发仅靶向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的途径特异性抑制剂。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环境中触发补体激活中起关键作用，特别是当经典途径在疾病发病机制中没有明显作用时。已经开发了MASP-2蛋白遗传缺陷的小鼠。MASP-2（-/-）小鼠和遗传匹配的MASP-2（+/+）小鼠的可用性提供了直接评价MASP-2和凝集素依赖性补体系统在CNV和AMD的鼠模型中的致病作用的有力研究工具。该SBIR资助申请的具体目的是比较和对比当在激光诱导的CNV（新生血管性AMD的加速模型）过程中评价MASP-2（-/-）和MASP-2（+/+）小鼠时获得的结果。I期研究中的成功结果将表明MASP-2是用于治疗CNV（湿性）形式的AMD的有吸引力的治疗靶标。II期申请将集中于开发对MASP-2具有特异性的基于阻断单克隆抗体的化合物作为AMD的潜在治疗剂。视网膜相关性黄斑变性（AMD）是55岁以后失明的主要原因，据估计，在美国有175万人患有这种疾病，另有700万人“处于危险之中”。在这项SBIR资助中，研究将评估一种名为MASP-2的治疗AMD的潜在新靶点。将在缺乏MASP-2的小鼠中进行研究以确定它们对AMD的易感性，并将为这作为AMD药物开发中的新靶点提供支持。