Novel Compounds for Reducing Brain A-Beta Levels via Enhanced Systemic Clearance

通过增强全身清除率降低大脑 A-β 水平的新型化合物

• 批准号: 8714773
• 负责人: TODD C ZION
• 金额: $ 24.99万
• 依托单位: AKSTON BIOSCIENCES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714773
• 关键词: Active Biological Transport; Address; Affect; Affinity; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Antibodies; Binding; Binding Proteins; Biodistribution; Brain; Canis familiaris; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Data; Data; Degradation Pathway; Dementia; Deposition; Disease; Disease Progression; Endocytosis; Engineering; Enzyme-Linked Immunosorbent Assay; Equilibrium; Excision; Feasibility Studies; Goals; Health; Healthcare Systems; Human; Immunoglobulin G; Infusion procedures; Injection of therapeutic agent; Intravenous; Lead; Left; Liver; Mammals; Metabolic Clearance Rate; Methodology; Modification; Mus; Pathway interactions; Peripheral; Phase; Plasma; Play; Primates; Production; Proteins; Reporting; Research Personnel; Role; Safety; Saline; Sampling; Scientist; Side; Small Business Innovation Research Grant; Technology; Therapeutic; Time; United States; abeta accumulation; aged; cisterna magna; cognitive function; cost; experience; glycosylation; liver function; macrophage; mannose receptor; monomer; neurotoxic; novel; prevent; research clinical testing; research study; reuptake; self assembly; sugar; therapeutic target; uptake

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by progressively worsening dementia eventually leading to death. It affects over five million people in the United States and costs the healthcare system over $200 billion per year. Currently there is no available therapy for slowing, reversing or preventing the disease. There is strong evidence suggesting that AD starts with the accumulation of the 4.5 kDa peptide, amyloid beta (Aβ), in the brain leading to concentration-dependent Aβ self-assembly into neurotoxic oligomers. Aβ accumulation in sporadic AD is related to a decreased net clearance rate of Aβ from the brain rather than Aβ overproduction. Despite the strong correlation between Aβ accumulation and AD progression, most amyloid-targeted therapeutic approaches have failed to demonstrate significant clinical benefits. However, most Aβ-targeted therapies have focused on removing specific forms of Aβ (e.g. plaques or oligomers), inhibiting Aβ production, or shifting the equilibrium distribution of Aβ between the brain and the periphery. Few, if any, attempts have been made to enhance Aβ brain clearance rates by sustainably increasing the irreversible systemic clearance and degradation of Aβ. Akston proposes to address this critical need by developing therapeutic candidates that specifically bind and remove Aβ from the body at a high enough rate to increase the net clearance of Aβ from the brain into the periphery and reduce the overall steady state amyloid burden throughout the body. The company will leverage its key scientists' extensive experience in chemical modification of biomolecules for targeted biodistribution. Therapeutic candidates that are chemically-engineered with various targeting moieties will be infused intravenously in aged beagle dogs to select a candidate with the highest potential to reduce peripheral Aβ levels. The main goal of this one-year Phase 1 feasibility study is to demonstrate that this candidate, when infused intravenously for two weeks in aged beagle dogs, can significantly reduce brain and CSF Aβ levels. This candidate could then be evaluated in large-animal and human clinical testing to determine if increased systemic A clearance can reverse or stall the degradation in cognitive function associated with AD.

描述（由申请人提供）：阿尔茨海默病（AD）的特征是逐渐恶化的痴呆症最终导致死亡。它影响了美国500多万人，每年花费医疗保健系统超过2000亿美元。目前还没有有效的治疗方法来减缓、逆转或预防这种疾病。有强有力的证据表明，AD始于4.5 kDa肽，淀粉样蛋白（Aβ）在大脑中的积累，导致浓度依赖性的Aβ自组装成神经毒性低聚物。散发性AD中a β的积累与大脑中a β净清除率的降低有关，而不是与a β过量产生有关。尽管Aβ积累与AD进展之间存在很强的相关性，但大多数淀粉样蛋白靶向治疗方法未能显示出显著的临床益处。然而，大多数针对Aβ的治疗都集中在去除特定形式的Aβ（如斑块或寡聚物），抑制Aβ的产生，或改变Aβ在大脑和外周之间的平衡分布。很少（如果有的话）尝试通过持续增加Aβ的不可逆全身清除和降解来提高Aβ脑清除率。Akston建议通过开发候选治疗药物来解决这一关键需求，这些候选治疗药物能够以足够高的速率特异性结合并从体内去除a β，从而增加从大脑到外周的a β净清除率，并减少整个身体的总体稳态淀粉样蛋白负担。该公司将利用其主要科学家在生物分子化学修饰方面的丰富经验来进行目标生物分布。经化学工程处理的治疗候选药物将被静脉注射到老年比格犬中，以选择一种最有可能降低外周a β水平的候选药物。这项为期一年的1期可行性研究的主要目标是证明，在老年比格犬中静脉注射该候选药物两周后，可以显著降低脑和脑脊液Aβ水平。这种候选药物可以在大型动物和人类临床试验中进行评估，以确定增加的系统性A清除是否可以逆转或延缓与AD相关的认知功能退化。