Novel Method for Alzheimer's Disease Drug Discovery

描述（由申请人提供）：我们的免疫系统起着“传感器”的作用，用于识别“外来”分子和生物体，如传染性病原体，并对它们进行攻击。如果我们能够“解读”免疫反应，使其与特定的疾病状态联系起来，那么就会产生一种非常有用的诊断工具。此外，对于由免疫反应引起或加剧的疾病状态，如果人们能够快速识别出攻击性抗体和/或T细胞，并识别出对它们特异性的中和分子，将导致这些疾病治疗的革命。这样就有可能特异性地阻断对特定抗原的反应。这项拟议的研究将开始，试图确定阿尔茨海默病（AD）特有的抗体，并将其与正常对照个体和帕金森病（PD）个体进行比较，后者将作为“神经变性对照组”。由于AD患者在几个区域表现出神经变性，并且神经变性与免疫系统激活相关，并且在AD和PD患者的血液中检测到与正常个体相比在量上略有不同的许多抗体，因此AD患者的血清中很可能存在许多对该疾病特异性的抗体，这可以产生用于治疗该疾病的主要候选药物。我们已经开发的筛选工具包括一个由数千个8聚体肽组成的肽微阵列。类肽是寡-N-取代的甘氨酸（即，侧链连接到主链氮而不是α-碳上）。这使得它们对蛋白酶具有免疫力，并且比肽更具有细胞渗透性。然而，类肽保留了肽的结合特征。我们有三个具体目标：（1）鉴定准确区分AD患者血清中抗体的类肽;（2）鉴定捕获“信息性”AD相关IgG和/或IgM抗体的特异性类肽;和（3）使用“信息性”类肽，我们将鉴定AD相关抗体。有了这些知识，可以进行未来的实验，以确定是否可以使用信息类肽来中和模型系统中的抗体，从而显示出作为新型AD药物的潜力。公共卫生相关性：该项目的目标是开始开发用于治疗阿尔茨海默病（AD）的主要候选药物的过程。在AD患者的血液中已经鉴定出淀粉样β肽的抗体，并且该抗体已用于治疗目的。我们将开始使用一种新的筛选工具，一种肽阵列，寻找和鉴定AD患者血液中的抗体，这些抗体是该疾病特有的。本研究开始了提供以下机制的途径：（1）在不预知疾病分子机制的情况下鉴定血清中与AD相关的自身抗体，以及（2）分离与疾病状态相关的抗原。鉴于免疫系统已知或可能反应的疾病状态范围广泛，该技术可以提供具有非凡实用性和范围的医学诊断平台。下游抗原鉴定研究可以提供有关疾病过程生物学的新信息。同样或更重要的是，一些“高信息含量”类肽可能捕获导致疾病或疾病进展的抗体（例如，与脑炎症相关的抗体）。因此，捕获类肽是能够选择性中和这些抗体而通常不抑制整体免疫应答的化合物的直接先导物。发现高度特异性免疫调节剂的技术可能会改变AD的治疗。

DESCRIPTION (provided by applicant): Our immune system functions as a "sensor", acting to identify "alien" molecules and organisms such as infectious agents and to mount attacks upon them. If we could "read" immune responses in such a way that they could be linked to specific disease states, a diagnostic tool of extraordinary utility would result. Furthermore, for disease states that are brought about or exacerbated by an immune response, if one could rapidly identify the offending antibodies and/or T-cells, and identify neutralizing molecules specific for them, a revolution in the treatment of these diseases would result. Then it would be possible to specifically interdict responses to specific antigens. The proposed study will begin by attempting to identify antibodies that are unique to Alzheimer's disease (AD), and compare them with normal control individuals, and individuals with Parkinson's disease (PD), which will serve as a "neurodegeneration control group". Because AD patients exhibit neurodegeneration in several rain regions, and neurodegeneration is associated with immune system activation, and a number of antibodies have been detected in the blood of AD and PD patients that differ somewhat in amounts compared to normal individuals, there may well be numerous antibodies in the serum of AD patients that are specific to the disease, which can give rise to lead candidate drugs for the treatment of the disease. The screening tool that we have developed involves a peptoid microarray, consisting of thousands of 8-mer peptoids. Peptoids are oligo-N-substituted glycines (i.e., the side chain is attached to the main chain nitrogen rather than the alpha-carbon). This renders them immune to proteases and far more cell-permeable than peptides. However, peptoids retain the binding characteristics of peptides. We have three specific aims: (1) identify peptoids that accurately discriminate antibodies in the serum of AD patients; (2) identify the specific peptoids that capture the "informative" AD-related IgG and/or IgM antibodies; and (3) using the "informative" peptoids, we will identify the AD-related antibodies. With this knowledge, future experiments can be undertaken to determine whether the informative peptoids can be used to neutralize the antibodies in model systems and thereby show potential as novel AD medications. PUBLIC HEALTH RELEVANCE: The goal of this project is to begin the process of developing lead candidate drugs for the treatment of Alzheimer's disease (AD). Antibodies to the amyloid-beta peptide have been identified in the blood of AD patients, and this antibody has been used for therapeutic purposes. We will begin by using a novel screening tool, a peptoid array, to look for and identify antibodies in the blood of AD patients that are unique to the disease. This study begins the pathway that provides a mechanism to: (1) identify auto-antibodies in serum that are associated with AD without foreknowledge of the molecular mechanism of the disease, and (2) isolate antigens associated with the disease state. Given the wide range of disease states to which the immune system is known, or is likely to react, this technology could provide a medical diagnostics platform of extraordinary utility and scope. The downstream antigen identification studies could provide new information on the biology of the disease process. Of equal or greater importance, it is likely that some of the "high information content" peptoids capture the antibodies that are causative of the disease, or of disease progression (e.g., antibodies related to brain inflammation). Thus, the capture peptoids are immediate leads for compounds capable of selectively neutralizing these antibodies without generally dampening the overall immune response. A technology for the discovery of highly specific immunomodulatory agents could transform the treatment of AD.