MASP-2 Therapy for Macular Degeneration

描述（由申请人提供）：总体目标是开发能够阻断人MASP-2功能的单克隆抗体为基础的化合物，作为治疗年龄相关性黄斑变性（AMD）的潜在治疗剂。MASP-2是通过凝集素途径激活补体所必需的血浆丝氨酸蛋白酶，可能是开发炎症疾病新疗法的一个有吸引力的靶点。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可引发强烈的炎症反应，这被认为是在许多疾病状态下显著导致不希望的组织损伤的原因。最近的研究结果表明，补体激活在AMD的发病机制，特别是脉络膜新生血管（CNV）最严重的AMD的发病机制中起着核心作用。补体激活有三种途径：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，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。人类供体组织的免疫组织学研究表明，经典途径在AMD的补体激活中不起主要作用。最近的研究表明，在许多组织损伤情况下，凝集素途径可能在触发补体激活方面发挥关键作用，特别是在经典途径在疾病发病机制中没有明显作用的情况下。一种基因缺乏MASP-2蛋白的小鼠已经被开发出来。MASP-2（-/-）小鼠和遗传匹配的MASP-2（+/+）小鼠的可用性为直接评估MASP-2和凝集素依赖性补体系统在小鼠CNV和AMD模型中的致病作用提供了有力的研究工具。这项SBIR拨款申请的具体目的是比较和对比MASP-2（-/-）和MASP-2（+/+）小鼠在激光诱导CNV（一种新生血管性AMD的加速模型）过程中获得的结果。I期研究的成功结果将表明，MASP-2是治疗CNV（湿）型AMD的一个有吸引力的治疗靶点。II期申请将专注于开发maasp -2特异性的基于阻断单克隆抗体的化合物，作为AMD的潜在治疗药物。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，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。研究将在缺乏MASP-2的小鼠中进行，以确定它们对AMD的易感性，并将为其作为AMD药物开发的新靶点提供支持。

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.