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

描述(申请人提供)：阿尔茨海默病(AD)的特征是痴呆症逐渐恶化，最终导致死亡。它影响着美国500多万人，每年给医疗保健系统造成超过2000亿美元的损失。目前还没有减缓、逆转或预防这种疾病的可用的治疗方法。有强有力的证据表明，AD始于4.5kDa的淀粉样β蛋白(Aβ)在大脑中的积累，导致Aβ浓度依赖地自组装成神经毒性低聚物。散发性AD中β的积聚与Aβ从大脑中的净清除率降低有关，而不是与Aβ的过量生产有关。尽管Aβ积聚与AD进展密切相关，但大多数以淀粉样蛋白为靶点的治疗方法未能显示出显著的临床疗效。然而，大多数针对Aβ的治疗侧重于去除特定形式的Aβ(例如斑块或寡聚体)，抑制Aβ的产生，或改变Aβ在大脑和外周之间的平衡分布。几乎没有人试图通过可持续地增加Aβ的不可逆转的全身清除和降解来提高Aβ的脑清除率。阿克斯顿建议通过开发治疗候选药物来满足这一关键需求，该候选药物能够以足够高的速度专门结合和从体内移除Aβ，以增加Aβ从大脑到外周的净清除，并减少整个身体的整体稳定状态淀粉样蛋白负担。该公司将利用其关键科学家在生物分子化学修饰方面的丰富经验，进行有针对性的生物分布。具有不同靶向部分的化学设计的治疗候选者将被静脉注射到老年比格犬体内，以选择具有最高潜力降低外周Aβ水平的候选者。这项为期一年的第一阶段可行性研究的主要目标是证明，当该候选药物在老年比格犬体内静脉输注两周时，可以显著降低大脑和脑脊液Aβ水平。然后，可以在大型动物和人类临床试验中对该候选药物进行评估，以确定增加全身A蛋白清除量是否可以逆转或延缓与AD相关的认知功能退化。

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.