Amyloid Inhibiting Agent for Treatment of Alzheimer's

阿尔茨海默病（AD）是一种退行性脑部疾病，临床表现为记忆力、认知、推理、判断和情绪稳定性的进行性丧失，逐渐导致严重的精神退化，最终导致死亡。阿尔茨海默病是老年人痴呆症的主要原因，目前影响着400万至500万美国人，预计未来25年发病率将翻一番。阿尔茨海默病的特征是脑内积聚了含有β -淀粉样蛋白（Abeta）的不溶性纤维样淀粉样沉积物，以细胞外淀粉样斑块的形式存在于脑实质或血管壁中。Abeta淀粉样蛋白在大脑中的形成、沉积和持续被认为在AD的发病机制中起着核心作用，导致神经元丢失和记忆功能障碍，因此已成为开发治疗AD及相关疾病的新药的中心靶点。阿尔茨海默病目前没有治愈或有效的治疗方法，患者通常在发病后3-10年内死亡。我们之前的研究已经鉴定出一种来自亚马逊雨林木本藤本植物Uncaria tomentosa（即猫爪）的天然物质，称为PTI-00703，它是一种有效的Abeta原纤维形成/生长抑制剂，并导致预先形成的Abeta原纤维的破坏/解体。在我们的I期研究中，我们使用了分析引导分离和高效液相色谱法来分离、测试和表征PTI-00703中具有强效AB纤维生成抑制活性的活性成分。许多主要成分（统称为PTI-777）被纯化并在相关的体外和动物模型试验中进行了测试，发现具有极其有效的抑制β纤维生成活性。在II期研究中，我们将完成每个PTI-777活性成分的结构鉴定和临床前研究，包括体外和体内血脑屏障渗透研究，使用相关的大鼠和产生斑块的转基因小鼠模型来确定对预防和清除脑淀粉样斑块的潜在抑制作用，啮齿动物的行为研究，以及安全性/毒理学。以及生物分布研究，最终确定临床候选药物。这些研究预计将导致确定一种新的候选药物，用于治疗阿尔茨海默病和相关疾病的β淀粉样变性，其中涉及使用天然衍生化合物。从这些研究中获得的知识还将确定设计用于治疗AD和其他淀粉样病的新型抗淀粉样蛋白疗法所需的结构参数。拟议的商业应用：阿尔茨海默病（AD）目前影响着4-5百万美国人，估计耗资800 - 1000亿美元。目前，没有治愈或有效的治疗方法，患者通常在发病后3- 10年内死亡。一种天然植物来源的β淀粉样蛋白纤维形成抑制剂的鉴定有望导致治疗AD和相关疾病的新药的开发。

Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million Americans, which is expected to double in incidence in the next 25 years. AD is characterized by the brain accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (Abeta), either as extracellular amyloid plaques in the brain parenchyma or in blood vessel walls. Abeta amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore has become a central target for the development of new drugs for the treatment of AD and related disorders. In AD, there is currently no cure or substantially effective treatment, and the patient usually dies within 3-10 years from disease onset. Our previous studies has led to the identification of a natural substance derived from the amazon rain forest woody vine, Uncaria tomentosa (i.e. Cat's claw), referred to as PTI-00703, which acts a potent inhibitor of Abeta fibril formation/growth, and causes disruption/disassembly of pre-formed Abeta fibrils. In Phase I of our studies, we used assay guided fractionation and HPLC to isolate, test and characterize active ingredients within PTI-00703 that possess potent AB fibrillogenesis inhibitory activity. A number of major ingredients (collectively known as PTI-777) were purified and tested in relevant in vitro and animal model assays, and found to possess extremely potent Abeta fibrillogenesis inhibitory activity. In Phase II proposed studies, we will complete structural identification of each of the PTI-777 active components, and pre-clinical studies including in vitro and in vivo blood-brain-barrier penetration studies, use of relevant rat and plaque- producing transgenic mouse models to determine potential inhibitory effects on prevention and clearance of brain amyloid plaques, behavioral studies in rodents, and safety/toxicology, and biodistribution studies for the ultimate identification of a clinical drug candidate. These studies are anticipated to lead to the identification of a new drug candidate for the treatment of Abeta amyloidosis in AD and related disorders which involves use of a naturally-derived compound. Knowledge gained from these studies will also identify structural parameters necessary for the design of new anti-amyloid therapeutics for the treatment of AD and other amyloidoses. PROPOSED COMMERCIAL APPLICATIONS: Alzheimer's disease (AD) currently affects 4-5 million Americans, at an estimated cost of $80-$100 billion. Currently, there is no cure or substantially effective treatment, and the patient usually dies within 3- 10 years from disease onset. Identification of a natural plant-derived inhibitor of Abeta amyloid fibrillogenesis is anticipated to lead to the development of a new drug(s) for the treatment of AD and related disorders.