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）：总体目标是开发基于单克隆抗体的化合物，能够阻止人Masp-2作为治疗年龄相关黄斑变性（AMD）的潜在治疗剂。 MASP-2是通过凝集素途径进行补体激活所需的血浆丝氨酸蛋白酶，可能是开发新型炎性疾病疗法的有吸引力的靶标。补体系统是重要的宿主防御机制。但是，过度或不受控制的补体激活会引发强烈的炎症反应，这被认为显着造成了许多疾病状态的不良组织损害。最近的结果暗示补体在AMD发病机理中，尤其是脉络膜新生血管形成（CNV）中最严重的AMD形式的核心作用。已经描述了三个途径以补体激活：经典，替代和凝集素途径。为了治疗AMD，希望开发特定途径的抑制剂，这将仅针对补体途径，导致特定病理，而不会完全关闭补体的免疫防御能力。人类供体组织的免疫组织学研究表明，经典途径在触发AMD中补体激活中不起作用。最近的研究表明，凝集素途径在许多组织损伤环境中触发补体激活中可能具有关键作用，尤其是在经典途径在疾病发病机理中没有明显作用的情况下。已经开发了MASP-2蛋白中的小鼠遗传缺陷型。 MASP-2（ - / - ）小鼠的可用性以及遗传匹配的MASP-2（+/+）小鼠提供了一种强大的研究工具，可直接评估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。本SBIR赠款应用程序中的特定目标是在激光诱导的CNV过程中评估MASP-2（ - / - ）和MASP-2（+/+）小鼠时获得的结果，这是新生血管AMD的加速模型。在I期研究中的成功结果表明，MASP-2是治疗AMD的CNV（湿）形式的有吸引力的治疗靶标。 II期应用将着重于开发针对MASP-2作为AMD的潜在治疗剂的基于单克隆抗体的化合物的开发。与年龄相关的黄斑变性（AMD）是55岁以后失明的主要原因，据估计，在美国，有175万个人患有这种疾病，另有700万个处于危险之中。在这项SBIR赠款中，研究将评估一个名为MASP-2治疗AMD的潜在新目标。将在缺乏MASP-2的小鼠中进行研究，以确定其对AMD的敏感性，并将为此提供支持，以此作为AMD药物开发的新目标。