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

描述(申请人提供)：阿尔茨海默病(AD)是一种进行性大脑疾病，通常被称为老年痴呆症。已有超过450万美国人被诊断出患有阿尔茨海默病，预计这一数字在未来40-50年内将增加两倍。目前还没有治愈阿尔茨海默病的方法。目前治疗阿尔茨海默病的方法是有症状的，并不干扰潜在疾病进程的不可阻挡的进展。迫切需要干预措施，以改善症状和减缓疾病进展。阿尔茨海默病的两个神经病理特征是A2多肽和tau在脑内的异常聚集和沉积，分别为细胞外神经炎斑块(NP)和细胞内神经纤维缠结(NFT)。在大脑中，单体抗体多肽和tau蛋白聚集形成高相对分子质量、可溶的多聚体神经毒性抗体和tau物种。多聚体抗体和tau物种的不断聚集导致抗体和tau分别沉积到NP和NFT中。最近的实验证据表明，阿尔茨海默病患者认知功能障碍可能与脑内可溶性高分子量(HMW)低聚体A2和tau类物质的积累有关，而不是NP和NFT本身的沉积。我们最近证实了一种精选的葡萄籽多酚提取物(GSPE)，即MegaNatural-Az(R)GSPE，能够有效地抑制抗体多肽和tau蛋白的聚集。因此，MegaNatural-Az(R)GSPE可能通过减轻抗体和tau介导的神经毒性反应而使AD受益。基于这一点和证据，MegaNatural-Az(R)在实验室动物和人类身上长期应用的耐受性和安全性都很高。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，以探索用于治疗AD的MegaNatural-Az(R)的开发。特别是，我们建议的研究将在AD患者中建立Meganattal-Az(R)GSPE的安全性和药代动力学。这项拟议的研究将提供必要的人体数据，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有效性。 与公共健康相关：这是一个研究开发一种精选葡萄籽提取物的可行性的应用，被称为MegaNatural-Az(R)，用于治疗阿尔茨海默氏症。Meganattal-AZ(R)已被证明在实验的体外和动物AD模型系统中通过有效地干扰β-淀粉样多肽和tau蛋白聚集成神经毒性聚集体而有利于AD的表型。这项研究将评估MegaNatural-Az(R)在AD患者中的安全性、药代动力学，并在为期10周的多剂量递增研究中探索治疗效果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.