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

描述(由申请人提供)：突触丢失是阿尔茨海默病(AD)的早期特征，先于神经元丢失和预测认知缺陷。Annexon的联合创始人Ben Bares博士已经确定，经典的补体蛋白C1q在AD大脑中上调约70倍，是神经系统突触丢失的关键媒介。此外，在AD、青光眼和中风的啮齿动物模型中，C1q的遗传消融被证明具有保护作用，最近发现相关的补体途径基因与AD的易感性有关。这一第一阶段计划的目标是识别抑制C1q及其相关蛋白C1s的单抗，并准备在AD动物模型中进行测试。具体地说，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。然后这些抗体将被测试其抑制作用的能力 用体外补体功能测定测定小鼠和人补体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。 公元一代的。在小鼠身上的治疗效果的证明将为这些抗体的临床开发提供理论基础。 与公共卫生相关：突触丢失是阿尔茨海默病(AD)的一个标志。它先于神经元细胞丢失，并预测认知偏向。经典的补体途径蛋白在衰老的大脑中上调约10倍，在阿尔茨海默病患者的大脑中上调约70倍。此外，这一途径最近被证明是消除正常小鼠突触所必需的，在这些小鼠中，经典补体基因被基因去除的小鼠对阿尔茨海默病具有部分抵抗力。我们正在开发经典补体级联的药物抑制剂，并将在AD的动物模型中进行测试。

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.