Drug Development of an Alzheimer's disease brain scan

阿尔茨海默病脑部扫描的药物开发

• 批准号: 6774704
• 负责人: RUBEN J. BOADO
• 金额: $ 45.28万
• 依托单位: ARMAGEN TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774704
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; amyloid proteins; bioimaging /biomedical imaging; biotechnology; blood brain barrier; brain imaging /visualization /scanning; cell line; chimeric proteins; diagnosis design /evaluation; drug design /synthesis /production; immunocytochemistry; mass spectrometry; matrix assisted laser desorption ionization; nervous system disorder diagnosis; protein engineering; tissue /cell culture; western blottings

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.

描述（由申请人提供）：阿尔茨海默病（AD）痴呆是由大脑中多年积累的淀粉样蛋白引起的。因此，开发测量大脑淀粉样蛋白的脑部扫描可以识别那些有后期发展为 AD 风险的个体。早期发现可以早期治疗并延迟症状的出现。据估计，仅将 AD 症状的出现延迟 5 年，美国每年就可以节省 500 亿美元的医疗费用。仅在美国，可能接受 AD 诊断性脑部扫描的人数就超过 3000 万。这项工作的目标是开发阿尔茨海默病 (AD) 诊断性脑扫描。 AD 是由淀粉样蛋白在大脑中沉积引起的，如果淀粉样蛋白显像剂能够通过血脑屏障 (BBB)，则可以对 AD 进行诊断性脑部扫描。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与靶向配体融合，该配体在体内经历受体介导的穿过血脑屏障的转运。这种 BBB 转运载体经过基因工程改造，可在人体中使用而不会产生免疫反应。该融合蛋白将是一种双功能分子，不仅可以穿过血脑屏障，还可以在体内与 AD 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，细胞系被产生，并且融合蛋白的双功能被证明——融合蛋白既结合BBB受体又结合AD淀粉样蛋白。第二阶段工作将产生分泌融合蛋白的细胞系，并且该蛋白的生产将扩大生产规模。融合蛋白验证后，将于03年进行药理学/毒理学和IND准备。 II 期工作的完成将为 FDA 准备 IND，以测试这种新颖的体内脑扫描，这将是第一个针对 AD 的诊断测试。 AD 脑部扫描可以早期发现那些有脑淀粉样蛋白和 AD 后期发展风险的个体，并可以进行早期药物治疗。