Neurotoxin Discovery Platform - Drugs of Abuse

描述（由申请人提供）：本II期申请的目的 是开发一种敏感的定量生物标志物， 退化，特别是与滥用药物有关。我们已经证明 在神经元变性过程中，神经元定位的蛋白质MAP-tau 蛋白水解切割（C-tau）在头部创伤和中风患者中的作用。我们 已经开发出了特异性识别C-tau的抗体。使用C-tau ELISA和免疫组织化学（IHC）1期研究表明， 神经毒性剂量的甲基苯丙胺脑C-tau水平在一段时间内增加 老鼠的依赖性更多的研究首次证明， MDMA（摇头丸）是一种神经毒素。我们 定量C-tau研究表明，MDMA的神经毒性仅为3%， 在甲基苯丙胺之后看到的， 研究证明MDMA神经毒性。拟议的研究将验证 我们的C-tau神经毒素生物标志物，通过评估神经毒性的时间过程， 三种街头毒品（MDMA，PMA和PCP粉尘），一种环境神经毒素 (TMT)和神经毒性的“黄金标准”--红藻氨酸 具体目标1-产品开发：进行质量控制研究， C-tau ELISA和IHC试剂盒的质量控制生产。 具体目标2-产品利用：确定C-tau是否可靠定量 由滥用药物和环境神经毒素引起的神经毒性。 滥用药物（MDMA、PMA、PCP）的神经毒性剂量，环境 神经毒素（TMT）和红藻氨酸（“黄金标准”）将被管理， 通过ELISA定量神经毒性的时间过程，并通过 C-tau免疫组化。 拟议的商业应用：我们的目标是开发一种敏感的生物标志物，用于定量药物诱导的神经元变性。 国家药物滥用研究所指出，“需要改进方法，以查明、评估和量化滥用药物的神经毒性的性质和程度”。目前，鉴定药物诱导的动物神经毒性的主要方法是选择性银染色法。 这种方法是组织化学和非定量的。 我们的产品将是定量的（ELISA）和更敏感的比现有的银染色技术检测药物诱导的神经毒性，采用免疫组织化学。 我们的产品有几个市场（C-tau ELISA和C-tau免疫组织化学）。 神经毒素、神经退行性疾病、头部损伤或中风的动物研究将是我们C-tau技术的用户。 2000年，Medline指出，在这些领域发表了4，254项研究，估计年市场规模为420万美元。

DESCRIPTION (provided by applicant): The objective of this Phase II application is to develop a sensitive quantitative biomarker of drug-induced neuronal degeneration, particularly associated with drugs of abuse. We have shown that during neuronal degeneration the neuronally localized protein MAP-tau is proteolytically cleaved (C-tau) in patients with head trauma and stroke. We have developed antibodies that specifically recognize C-tau. Employing C-tau ELISA and immunohistochemistry (IHC) Phase 1 studies demonstrate that after a neurotoxic dose of methamphetamine brain C-tau levels increase in a time dependent manner in the rat. Additional studies demonstrate for the first time, that MDMA ('ecstasy') is a neurotoxin utilizing our C-tau ELISA. Our quantitative C-tau studies indicate that MDMA neurotoxicity is only 3 percent of that seen after methamphetamine accounting for the inability of previous studies to demosnstrate MDMA neurotoxicity. The proposed studies will validate our C-tau neurotoxin biomarker by assessing the time course of neurotoxicity of three street drugs (MDMA, PMA and PCP dust']), an environmental neurotoxin (TMT) and a neurotoxicity 'Gold Standard'-kainic acid. Specific Aim 1-Product Development: Perform quality control studies and quality-controlled manufacturing of C-tau ELISA and IHC kits. Specific Aim 2-Product Utilization: Determine if C-tau reliably quantifies neurotoxicity caused by drugs of abuse and environmental neurotoxins. Neurotoxic doses of drugs of abuse (MDMA, PMA, PCP), an environmental neurotoxin (TMT) and kainic acid ('Gold Standard') will be administered and the time course of neurotoxicity quantified by ELISA and anatomically localized by C-tau IHC. PROPOSED COMMERCIAL APPLICATION: Our objective is to develop a sensitive biomarker for quantifying drug-induced neuronal degeneration. The National Institute on Drug Abuse has indicated that "improved methods are needed for identifying, assessing and quantifying the nature and extent of neurotoxicity" of abused drugs. Currently, the primary method of identifying drug-induced neurotoxicity in animals is the selective silver stain method. This method is histochemical and non-quantitative. Our product will be both quantitative (ELISA) and more sensitive than available silver stain techniques for detecting drug-induced neurotoxicity employing immunohistochemistry. There are several markets for our product (C-tau ELISA and C-tau immunohistochemistry). Animal studies of neurotoxins, neurodegenerative diseases, head injury or stroke would be users of our C-tau technology. In the year 2000 Medline indicates there were 4,254 studies published in these areas for an estimated annual market size of $4.2 million dollars.