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

描述(申请人提供)：阿尔茨海默病(AD)是一种退行性大脑疾病，临床特征是记忆、认知、推理和判断的进行性丧失，逐渐导致严重的精神恶化，最终导致死亡。AD是导致老年人痴呆的主要原因，其特征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沉积。Aβ淀粉样蛋白在脑内的形成、沉积和持续存在被认为在AD的发病机制中起核心作用，导致神经元丢失和记忆功能障碍，因此是开发治疗AD和相关疾病的新疗法的中心靶点。我们先前的第一阶段研究首先在层粘连蛋白上发现了一个新的相关的Abeta结合位点，定位于层粘连蛋白A链上的球状结构域重复序列。合成了300多个重叠的跨越结合部位区域的12-13聚体多肽，并使用各种体外筛选方法进行测试，以确定显示出最有效的抗Aβ淀粉样蛋白抑制/破坏活性的最佳12-13聚体多肽。在第二阶段研究中，我们评估了排名前六位的12-13位多肽，并设计、合成、测试和鉴定了较小的6-9位多肽类似物，作为临床前的主要候选者。这些严格的研究现在已经发现了两种新的小7聚体D-氨基酸多肽，在相关的APP转基因斑块产生的AD动物模型中外周给药后，可以显著减少和清除大脑Aβ淀粉样蛋白负荷(50-70%)，并改善记忆力(28%-44%)。这项第二阶段的SBIR延续计划现在将在体外和体内进一步开发这两种新的7聚体临床前候选多肽，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(即鼻腔、静脉注射)和/或S.C.)，减少和清除大脑Aβ淀粉样蛋白以及改善记忆的剂量和时间依赖效应也将在APP转基因斑块产生的小鼠模型中进一步确定，该模型显示记忆缺陷与Aβ负荷增加。这些研究将帮助我们选择一种新型的临床前候选小肽(及其备份)，该小肽将被开发用于人类临床试验和商业化，并有望成为治疗AD和相关的Abeta淀粉样变性的令人兴奋的新疗法。

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.