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

层粘连蛋白衍生的蛋白质片段作为阿尔茨海默病淀粉样变性的抑制剂

基本信息

批准号：
7418215
负责人：
ALAN D. SNOW
金额：
$ 51.7万
依托单位：
PROTEOTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418215
关键词：
Acute Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acid Sequence Amino Acids Amyloid Amyloid Fibrils Amyloid beta-Protein Amyloidosis Animal Model Animals Antibodies Antigens Apolipoprotein E Area Back Basement membrane Binding Binding Sites Biochemical Biological Biological Assay Biomedical Research Blood - brain barrier anatomy Blood Vessels Blood capillaries Body Weight Brain Brain Diseases California Cessation of life Chemicals Circular Dichroism Clinical Clinical Trials Cognition Collaborations Complement Complement 1q Congo Red Cultured Cells Daily Dementia Deposition Deterioration Development Digestion Disease Disruption Dose Drug Kinetics Drug or chemical Tissue Distribution Effectiveness Elderly Electrophoresis Emotional Endopeptidases Ensure Enzyme-Linked Immunosorbent Assay Fluorescence Fluorometry Functional disorder Future Glial Fibrillary Acidic Protein High Pressure Liquid Chromatography Hippocampus (Brain)Human Image Analysis Immunofluorescence Immunologic In Vitro Injection of therapeutic agent Intranasal Administration Intravenous Judgment Label Laboratories Laminin Lead Ligands Liquid substance Localized London Membrane Proteins Memory Memory Loss Memory impairment Methods Microscopic Modeling Mus Mutation Neurons Nose Numbers Onset of illness Pathogenesis Pathologist Patients Peptide Hydrolases Peptide Synthesis Peptides Peripheral Permeability Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Plasma Play Protein Fragment Protein Sequence Analysis Psyche structure Radiolabeled Rodent Role Route Safety Screening procedure Senile Plaques Small Business Funding Mechanisms Small Business Innovation Research Grant Solid Staining method Stains Synaptophysin Testing Therapeutic Thioflavin T Time Tissues Toxic effect Transgenic Mice Transgenic Organisms Tritium United States Food and Drug Administration amyloid fibril formation amyloid formation analog base brain tissue capillary commercialization day design dosage extracellular fibrillogenesis improved in vivo inhibitor/antagonist intraperitoneal juvenile animal laminin A morris water maze mouse model neuron loss novel novel therapeutics peptide analog polarized light polysulfated glycosaminoglycan pre-clinical prevent promoter radiotracer research clinical testing subcutaneous tau Proteins treatment duration

项目摘要

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.

描述（由申请人提供）：阿尔茨海默病（AD）是一种退行性脑疾病，临床特征为记忆、认知、推理和判断的进行性丧失，逐渐导致严重的精神恶化并最终死亡。AD是老年人痴呆的主要原因，其特征在于含有β-淀粉样蛋白（Abeta）的不溶性纤维状淀粉样沉积物的脑积累。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而在AD发病机制中发挥中心作用，因此是开发用于治疗AD和相关病症的新疗法的中心靶标。我们之前的I期研究首先确定了一个新的和相关的Abeta结合位点，定位于层粘连蛋白A链上的球状结构域重复。合成了跨越结合位点区域的超过300个重叠的12- 13聚体肽，并使用多种体外筛选方法进行测试，以确定证明最有效的抗A β淀粉样蛋白抑制/破坏活性的最佳12- 13聚体肽。在II期研究中，我们评估了前六种12- 13聚体肽，并设计、合成、测试和鉴定了较小的6- 9聚体肽类似物，这些肽类似物可作为临床前候选药物。这些严格的研究现已鉴定出两种新的小7聚体D-氨基酸肽，其在AD的相关APP转基因斑块产生动物模型中外周施用后引起脑A β淀粉样蛋白负荷的显著减少和清除（50-70%），并改善记忆（28-44%）。该II期SBIR延续提案项目现在将在体外和体内进一步开发这两种新型7聚体临床前候选肽，以确定其药代动力学、血脑屏障通透性和毒性特征。最佳给药途径（即鼻、i. v.和/或s.c.），还将在APP转基因噬斑产生小鼠模型中进一步确定减少和清除脑A β淀粉样蛋白和改善记忆的剂量和时间依赖性功效，所述小鼠模型证明记忆缺陷伴随A β负荷增加。这些研究将帮助我们选择一种新的小肽临床前候选药物（及其备份），该药物将用于人体临床试验和商业化，并有望成为AD和相关Abeta淀粉样变性的令人兴奋的新治疗方法。