Drug Development of an Alzheimer's disease brain scan

描述(申请人提供)：阿尔茨海默病(AD)的痴呆症是由大脑中多年的淀粉样蛋白积聚引起的。因此，开发一种测量大脑淀粉样蛋白的脑部扫描可以识别那些有可能患上阿尔茨海默病的人。早期发现可以导致早期治疗，并推迟症状的出现。据估计，将AD症状出现的时间推迟5年，每年将为美国节省500亿美元的医疗费用。仅在美国，有可能接受AD诊断脑扫描的人数就超过3000万人。这项工作的目标是开发一种艾兹海默氏症(AD)诊断脑扫描。AD是由淀粉样蛋白在大脑中的沉积引起的，如果淀粉样蛋白显像剂可以通过血脑屏障(BBB)运输，就可以开发出诊断AD的脑扫描。这项工作将制备一种基因工程融合蛋白，其中淀粉样蛋白显像剂与靶向配体融合，后者在体内经历受体介导的跨血脑屏障转运。这种血脑屏障运输载体经过基因工程改造，可以在没有免疫反应的情况下在人类身上使用。融合蛋白将是一个双功能分子，不仅可以跨越血脑屏障，还可以在体内与AD大脑的淀粉样斑块结合，并含有用于放射性标记的螯合剂部分。在第一阶段，融合基因被设计出来，细胞系被生产出来，融合蛋白的双功能被证明--融合蛋白既与BBB受体结合，又与AD淀粉样蛋白结合。第二阶段的工作将产生一种分泌融合蛋白的细胞系，这种蛋白的生产将被放大用于生产。在确认融合蛋白后，将在03年内进行药理学/毒理学和IND准备工作。第二阶段工作的完成将使FDA能够准备一份IND，用于测试这一新颖的活体脑扫描，这将是第一个专用于AD的诊断测试。AD脑扫描可能会及早发现那些有可能患上脑淀粉样蛋白和AD的人，并允许及早进行药物治疗。

DESCRIPTION (provided by applicant): The dementia of Alzheimer's Disease (AD) is caused by the buildup in the brain over many years of amyloid. Therefore, the development of a brain scan that measures brain amyloid could identify those individuals at risk for the later development of AD. Early detection can lead to early therapy and delay the onset of symptoms. It is estimated that the delay of the onset of symptoms of AD, for just 5 years, would save $50 billion per year in U.S. health care costs. The number of people who are potential candidates for an AD diagnostic brain scan is in excess of 30 million in United States alone. The goal of this work is the development of an AIzheimer's Disease (AD) diagnostic brain scan. AD is caused by the deposition of amyloid in the brain and a diagnostic brain scan for AD could be developed if amyloid imaging agents were made transportable through the blood brain barrier (BBB). This work will prepare a genetically engineered fusion protein wherein the amyloid-imaging agent is fused to a targeting ligand that undergoes receptor-mediated transport across the BBB in vivo. This BBB transport vector has been genetically engineered to enable use in humans without immunological reaction. The fusion protein will be a bi-functional molecule that not only crosses the BBB, but also binds to the amyloid plaques of AD brain in vivo, and contains a chelator moiety for radiolabeling. In phase I, the fusion gene was engineered, cell lines were produced, and the bi-funtionality of the fusion protein was demonstrated--the fusion protein both binds the BBB receptor and binds the AD amyloid. The phase II work will produce a cell line secreting the fusion protein, and the production of this protein will be scaled up for manufacturing. Following the validation of the fusion protein, the pharmacology/toxicology and IND preparation will be performed during the 03 year. The completion of the phase II work will enable the preparation of an IND to the FDA for testing of this novel in vivo brain scan that will be the first diagnostic test specific for AD. The AD brain scan may allow for the early detection of those individuals at risk for later development of brain amyloid and AD, and allow for early drug therapy.