Development of novel inhibitors of complement for the treatment of Alzheimer's Di

开发治疗阿尔茨海默病的新型补体抑制剂

• 批准号: 8393513
• 负责人: Arnon Rosenthal
• 金额: $ 16.7万
• 依托单位: ANNEXON, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393513
• 关键词: Ablation; Adult; Alzheimer' s Disease; Animal Model; Antibodies; Antibody Formation; Binding; Biological Assay; Blocking Antibodies; Brain; Classical Complement Pathway; Clinical; Clinical Research; Cognitive; Cognitive deficits; Complement; Complement 1q; Complement Activation; Complement Hemolytic Activity Assay; Complement Inactivators; Complement component C1s; Conditioned Culture Media; Cytolysis; Development; Embryonic Development; Enzyme-Linked Immunosorbent Assay; Enzymes; Epitopes; Erythrocytes; Generations; Genes; Genetic; Genetic Polymorphism; Genome; Glaucoma; Goals; Hemolysis; Human; Hybridomas; Immune system; Immunization; Knockout Mice; Measures; Mediating; Mediator of activation protein; Monoclonal Antibodies; Mus; Nervous system structure; Neurons; Pathway interactions; Patients; Peptides; Phage Display; Phase; Plasma; Play; Predisposition; Procedures; Production; Protein Isoforms; Proteins; Resistance; Rodent Model; Screening procedure; Stroke; Surveys; Synapses; Technology; Testing; Therapeutic; Therapeutic Effect; Work; aging brain; complement pathway; humanized antibody; in vitro Assay; in vitro activity; in vivo; inhibitor/antagonist; mouse model; neuron loss; novel; prevent; research study; site-specific integration; stable cell line

DESCRIPTION (provided by applicant): The loss of synapses is an early hallmark of Alzheimer's disease (AD) preceding neuronal loss and predicting cognitive deficit. Dr Ben Bares, Annexon co-founder, has determined that the classical complement protein C1q, which is up regulated ~70 fold in the AD brain, is a critical mediator of synapse loss in the nervous system. Moreover genetic ablation of C1q was shown to be protective in rodent models for AD, glaucoma, and stroke and related complement pathway genes were recently shown to be associated with susceptibility to AD. The goal of this Phase 1 proposal is to identify monoclonal antibodies that inhibit C1q and its associated protein C1s and prepare them for testing in animal models of AD. Specifically, we are using mouse hybridoma and phage display to isolate antibodies that bind C1q and C1s. These antibodies will then be tested for their ability to inhibit the activity of mouse and human C1q and C1s using in vitro assays of complement function. Phase II of the project will evaluate the therapeutic potential of these inhibitors in mouse models of AD. Demonstration of a therapeutic effect in mice will provide a rationale for clinical development of these antibodies. PUBLIC HEALTH RELEVANCE: Synapse loss is a hallmark of Alzheimer's disease (AD). It precedes neuronal cel los and predicts cognitive deflect. The classical complement pathway proteins are up-regulated ~10 fold in the aging brain and ~70 fold the brains of Alzheimer's patients. Moreover, this pathway was recently shown to be required for the elimination of synapses in normal mice and mice in which classical complement genes were genetically ablated are partially resistant to Alzheimer's disease. We are developing pharmacological inhibitors of the classical complement cascade and will test them in animal models of AD.

描述（由申请人提供）：突触丧失是阿尔茨海默病（AD）的早期标志，先于神经元丧失并预测认知缺陷。Annexon联合创始人Ben Bares博士已经确定，经典补体蛋白C1q在AD大脑中上调约70倍，是神经系统突触丢失的关键介质。此外，在AD、青光眼和中风的啮齿动物模型中，C1q的基因消融显示出保护作用，并且最近显示相关补体途径基因与AD易感性相关。该第1阶段提案的目标是鉴定抑制C1q及其相关蛋白C1s的单克隆抗体，并准备在AD动物模型中进行测试。具体来说，我们正在使用小鼠杂交瘤和噬菌体展示来分离结合C1q和C1s的抗体。然后将测试这些抗体抑制 使用体外补体功能测定法测定小鼠和人C1q和C1s的活性。该项目的第二阶段将评估这些抑制剂在小鼠模型中的治疗潜力 的AD。在小鼠中的治疗效果的证明将为这些抗体的临床开发提供依据。 公共卫生相关性：突触丢失是阿尔茨海默病（AD）的标志。它先于神经元细胞并预测认知偏差。经典补体途径蛋白在老化的大脑中上调约10倍，在阿尔茨海默病患者的大脑中上调约70倍。此外，该途径最近被证明是消除正常小鼠中的突触所必需的，并且其中经典补体基因被遗传消融的小鼠对阿尔茨海默病具有部分抗性。我们正在开发经典补体级联反应的药理学抑制剂，并将在AD动物模型中进行测试。