Amyloid Inhibiting Agent for Treatment of Alzheimer's

阿尔茨海默病（Alzheimer's disease，AD）是一种脑退行性疾病，临床上表现为记忆、认知、推理、判断和情绪稳定性的进行性丧失，逐渐导致严重的智力衰退并最终死亡。AD是老年痴呆症的主要原因，目前影响着400万至500万美国人，预计在未来25年内发病率将翻一番。AD的特征在于含有β-淀粉样蛋白（Abeta）的不溶性纤维状淀粉样沉积物的脑积聚，作为脑实质或血管壁中的细胞外淀粉样斑块。据信，脑中的A β淀粉样蛋白形成、沉积和持续存在通过促进神经元损失和记忆功能障碍在AD发病机制中发挥中心作用，因此已成为开发用于治疗AD和相关病症的新药的中心靶标。在AD中，目前没有治愈或实质上有效的治疗，并且患者通常在疾病发作后3-10年内死亡。我们先前的研究已经导致鉴定出来源于亚马逊雨林木本藤本植物绒毛钩藤（即猫爪）的天然物质，称为PTI-00703，其充当Abeta原纤维形成/生长的有效抑制剂，并引起预形成的Abeta原纤维的破坏/分解。在我们研究的I期中，我们使用测定指导的分级分离和HPLC来分离、测试和表征PTI-00703中具有有效AB原纤维形成抑制活性的活性成分。许多主要成分（统称为PTI-777）在相关的体外和动物模型试验中进行了纯化和测试，发现具有极强的Abeta原纤维形成抑制活性。在II期拟定研究中，我们将完成每种PTI-777活性成分的结构鉴定，以及临床前研究，包括体外和体内血脑屏障渗透研究，使用相关大鼠和斑块产生转基因小鼠模型确定对预防和清除脑淀粉样蛋白斑块的潜在抑制作用，啮齿动物行为研究和安全性/毒理学，以及用于最终鉴定临床候选药物的生物分布研究。预计这些研究将导致识别出用于治疗AD和相关疾病中的A β淀粉样变性的新候选药物，其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和其他淀粉样变性的新的抗淀粉样蛋白治疗剂所必需的结构参数。拟议的商业应用：阿尔茨海默病（AD）目前影响着400万至500万美国人，估计成本为800亿至1000亿美元。目前，没有治愈或基本有效的治疗方法，患者通常在发病后3- 10年内死亡。预期A β淀粉样蛋白原纤维形成的天然植物来源的抑制剂的鉴定将导致用于治疗AD和相关病症的新药的开发。

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.