Drug Development of an Alzheimer's disease brain scan

描述（由申请人提供）：阿尔茨海默病（AD）的痴呆是由多年来淀粉样蛋白在大脑中的积累引起的。因此，测量大脑淀粉样蛋白的大脑扫描的发展可以识别出那些有后期发展为AD风险的个体。早期发现可以导致早期治疗并延迟症状的发作。据估计，AD症状发作的延迟仅5年，每年将节省美国医疗保健费用500亿美元。仅在美国，AD诊断脑扫描的潜在候选人人数就超过3000万。这项工作的目标是开发一种诊断阿尔茨海默病（AD）的大脑扫描。AD是由淀粉样蛋白在脑中的沉积引起的，如果淀粉样蛋白成像剂可通过血脑屏障（BBB）运输，则可以开发AD的诊断脑扫描。这项工作将制备一种基因工程融合蛋白，其中淀粉样蛋白成像剂融合到靶向配体，在体内经历受体介导的运输通过血脑屏障。这种BBB转运载体经过基因工程改造，能够在人体中使用而不产生免疫反应。融合蛋白将是一种双功能分子，不仅可以穿过BBB，而且可以在体内与AD脑的淀粉样斑块结合，并且含有用于放射性标记的螯合剂部分。在第一阶段，融合基因被工程化，细胞系被产生，并且融合蛋白的双功能性被证明-融合蛋白既结合BBB受体又结合AD淀粉样蛋白。第二阶段的工作将产生一个分泌融合蛋白的细胞系，这种蛋白的生产将扩大规模用于生产。在融合蛋白验证后，将在2003年期间进行药理学/毒理学和IND制备。第二阶段工作的完成将使IND的准备工作能够提交给FDA，用于测试这种新型的体内脑扫描，这将是第一种针对AD的诊断测试。AD脑扫描可以允许早期检测那些有后期发展脑淀粉样蛋白和AD风险的个体，并允许早期药物治疗。

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.