Laminin-Derived Protein Fragments as Inhibitors of Alzheimer's Amyloidosis

描述（由申请人提供）：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、推理和判断能力的进行性丧失，逐渐导致严重的精神衰退，最终导致死亡。阿尔茨海默病是老年人痴呆的主要原因，其特点是大脑中积累了含有β -淀粉样蛋白（Abeta）的不溶性纤维淀粉样蛋白沉积物。Abeta淀粉样蛋白在大脑中的形成、沉积和持续被认为在阿尔茨海默病的发病机制中发挥核心作用，导致神经元丧失和记忆功能障碍，因此是开发治疗阿尔茨海默病和相关疾病的新疗法的中心目标。我们之前的I期研究首先确定了层粘连蛋白上一个新的相关的β结合位点，该位点位于层粘连蛋白a链的球状结构域重复序列上。我们合成了300多个跨越结合位点的重叠12-13mer肽，并使用多种体外筛选方法进行了测试，以确定最佳的12-13mer肽，这些肽显示出最有效的抗β -淀粉样蛋白抑制/破坏活性。在II期研究中，我们评估了排名前六的12-13聚肽，并设计、合成、测试和鉴定了较小的6-9聚肽类似物，作为主要的临床前候选物。这些严谨的研究现在已经鉴定出两种新的小7mer d -氨基酸肽，在相关的APP转基因斑块产生AD动物模型中外周给药后，可显著减少和清除脑β淀粉样蛋白负荷（50-70%），并改善记忆（28-44%）。该二期SBIR延续计划项目将进一步在体外和体内研究这两种新型7元临床前候选肽，以确定它们的药代动力学、血脑屏障通透性和毒性特征。最佳给药途径（即鼻、静脉和/或s.c）、剂量和时间依赖的减少和清除脑β淀粉样蛋白和改善记忆的功效也将在APP转基因斑块产生小鼠模型中进一步确定，该模型显示记忆缺陷与β负担增加。这些研究将帮助我们选择一种新的小肽临床前候选物（及其备份），该候选物将用于人体临床试验和商业化，并且有望作为阿尔茨海默病和相关的β淀粉样变性的令人兴奋的新治疗方法。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, and judgment that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly and is characterized by the brain accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (Abeta). 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 is a central target for the development of new therapeutics for the treatment of AD and related disorders. Our previous Phase I studies first identified a new and relevant Abeta binding site on laminin localized to the globular domain repeats on the laminin A chain. Over 300 overlapping 12-13mer peptides spanning the binding site area were synthesized and tested using a varietry of in vitro screening methods to determine the best 12-13mer peptides demonstrating the most potent anti-Abeta amyloid inhibitory/disruptive activity. In Phase II studies, we assessed the top six 12-13mer peptides and designed, synthesized, tested and identified smaller 6-9mer peptide analogs that served as lead pre-clinical candidates. These rigorous studies have now led to the identification of two novel small 7mer D-amino acid peptides that following peripheral administration in a relevant APP transgenic plaque producing animal model of AD cause a marked reduction and clearance of brain Abeta amyloid load (by 50-70%), and improved memory (by 28-44%). This Phase II SBIR continuation proposal project will now further develop these two novel 7mer pre- clinical candidate peptides in vitro and in vivo to determine their pharmakokinetic, blood-brain-barrier permeability, and toxicity profiles. Best route of administration (i.e. nasal, i.v. and/or s.c.), dosage and time- dependent efficacy for reduction and clearance of brain Abeta amyloid and improved memory will also be further determined in the APP transgenic plaque-producing mouse model that demonstrates memory deficits with increased Abeta burden. These studies will help us select a novel small peptide pre-clinical candidate (and its backup) that will be developed for human clinical trials and commercialization, and that has the promise to serve as an exciting new treatment for AD and related Abeta amyloidosis.