Phase 11-Grape Seed Extract as Anti-Oligomerization Agent in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性脑疾病，通常称为老年性痴呆。超过450万美国人被诊断患有AD，预计这一数字在未来40-50年内将增加两倍。目前还没有治愈AD的方法。目前可用于AD的治疗是对症的，并且不干扰潜在疾病过程的不可阻挡的进展。迫切需要可能改善症状并改变疾病进展的干预措施。AD的两个定义性神经病理学特征是A2肽和tau在脑中的异常聚集和沉积，分别为细胞外神经炎斑（NP）和细胞内神经纤维缠结（NFT）。在脑中，单体Ab肽和tau蛋白聚集以形成高分子量、可溶性多聚体神经毒性Ab和tau种类。多聚体Ab和tau种类的连续进行性聚集导致Ab和tau分别沉积到NP和NFT中。最近的实验证据表明，可溶性高分子量（HMW）寡聚A2和tau物质在脑中的积累，而不是NP和NFT本身的沉积，可能与AD中的认知功能障碍特异性相关。我们最近证明了一种选择的葡萄籽多酚提取物（GSPE），即MegaNatural-Az（R）GSPE，有效地抑制Ab肽和tau蛋白的聚集。因此，MegaNatural-Az（R）GSPE可通过减轻Ab和tau介导的神经毒性反应而有益于AD。基于此，证据证明MegaNatural-Az（R）在实验室动物和人类中长期应用具有高耐受性和安全性。这项拟议的研究代表了基础科学研究实验室和西奈山医学院阿尔茨海默病临床核心之间的合作，以探索MegaNatural-Az（R）治疗AD的发展。特别是，我们提出的研究将确定Meganatural-Az（R）GSPE在AD受试者中的安全性和药代动力学。作为次要指标，我们还将评价治疗疗效的临床和生物标志物指标。拟议的研究将提供必要的人类数据，以指导未来研究的设计，以测试GSPE在缓解AD患者认知恶化方面的疗效。 公共卫生相关性：这是一个应用程序，以研究开发一种选择葡萄籽提取物的可行性，称为MegaNatural-AZ（R）用于治疗阿尔茨海默病。Meganatural -AZ（R）已被证明通过有效干扰β-淀粉样肽和tau蛋白聚集成神经毒性聚集体，在体外实验和动物AD模型系统中有益于AD表型。该研究将评估MegaNatural- AZ（R）在AD患者中的安全性、药代动力学，并在一项为期10周的多次剂量递增研究中探索治疗功效的认知和生物学指标。

DESCRIPTION (provided by applicant): Alzheimer Disease (AD) is a progressive brain disease known generally as senile dementia. More than 4.5 million Americans have been diagnosed with AD, and this number is expected to triple in the next 40-50 years. There is currently no cure for AD. The treatments available today for AD are symptomatic and do not interfere with inexorable progression of the underlying disease process. There is a desperate need for interventions that might improve symptoms and modify the disease progression. The two defining neuropatholic features of AD are abnormal aggregation and deposition of A2 peptides and tau in the brain as, respectively, extracellular neuritic plaques (NP) and intracellular neurofrillary tangles (NFT). In the brain, monomeric Ab peptides and tau proteins are aggregated to form high molecular weight, soluble multimeric neurotoxic Ab and tau species. Continual progressive aggregations of multimeric Ab and tau species result in deposition of Ab and tau into, respectively, NP and NFT. Recent experimental evidence indicates that it is the accumulation of soluble high- molecular weight (HMW) oligomeric A2 and tau species in the brain, rather than deposition of NP and NFT per se, may be specifically related to cognitive dysfunction in AD. We recently demonstrated that a select grape- seed polyphenol extract (GSPE), namely, MegaNatural-Az(R) GSPE to potently inhibit the aggregation of both Ab peptides and tau proteins. Thus, MegaNatural-Az(R) GSPE may benefit AD by mitigating both Ab- and tau- mediated neurotoxic responses. Based on this and evidence demonstrated the high tolerability and safety of long-term application of MegaNatural-Az(R) in both laboratory animals and in human. The proposed study represents collaboration between basic science research laboratories and the Alzheimer's Disease Clinical Core at the Mount Sinai School of Medicine to explore the development of MegaNatural-Az(R) for treating AD. In particular, our proposed study will establish safety and pharmacokinetics of Meganatural-Az(R) GSPE in AD subjects. As secondary measures, we will also evaluate clinical and biomarker indexes of therapeutic efficacy. The proposed study will provide the essential human data to guide the design of future studies to test the efficacy of GSPE in mitigating cognitive deterioration in AD patients. PUBLIC HEALTH RELEVANCE: This is an application to study the feasibility of developing a select grape seed extract, referred to as MegaNatural- Az (R) for treating Alzheimer's Disease. Meganatural -AZ (R) has been shown to benefit AD phenotypes in experimental in vitro and animal AD model systems by potently interfering with aggregation of beta-amyloid peptides and tau proteins into neurotoxic aggregates. The study will access safety, pharmacokinetics of MegaNatural- Az (R) in AD patients and explore cognitive and biological indices of therapeutic efficacy in a 10 week multiple dose escalation study.