2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans

2-羟基苄胺预防阿尔茨海默病：对人类的初步评估

基本信息

批准号：
9564351
负责人：
John A Rathmacher
金额：
$ 15.06万
依托单位：
METABOLIC TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9564351
关键词：
Address Adult Adverse effects Adverse event Affect Age-associated memory impairment Aging Aldehydes Alzheimer disease prevention Alzheimer&apos s Disease American Amination Amines Amyloid Amyloid beta-Protein Animals Avena sativa Biological Biological Availability Biological Markers Blood Blood Platelets Body Surface Area Brain Buckwheat Cause of Death Chemicals Clinical Clinical Pharmacology Clinical Research Clinical Trials Cognitive Collaborations Complete Blood Count Data Dendritic cell activation Development Diffuse Disease Disease Progression Dose Drug Kinetics Evaluation Functional disorder Goals High Density Lipoproteins Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Inflammation Injury Kidney Kinetics Ligands Lipid Peroxidation Lipid Peroxides Liver Lysine Malondialdehyde Measures Memory impairment Metabolic Metabolism Metals Monitor Mus Muscle N-methylacetamide-oxotremorine M Natural Products No-Observed-Adverse-Effect Level Nutritional Oral Oxidation-Reduction Oxidative Stress PTGS2 gene Pathogenesis Pathogenicity Pathway interactions Patients Penetrance Peptides Pharmacodynamics Plasma Post-Translational Protein Processing Preventive Preventive treatment Process Production Prostaglandin-Endoperoxide Synthase Proteins Reactive Oxygen Species Regimen Research Safety Seeds Short-Term Memory Spinal Puncture T-Lymphocyte Technology Testing Therapeutic Tissues Toxic effect Toxicology Transgenic Mice Validation adduct age related amyloid peptide base clinical toxicology crosslink curative treatments cyclooxygenase 1 disorder prevention effective therapy efficacy study experimental study immunoreactivity in vivo manufacturing process mild cognitive impairment mitochondrial dysfunction neurotoxic neurotoxicity novel pre-clinical preclinical development prevent protein folding protein function small molecule tau Proteins volunteer

项目摘要

Approximately 5.2 million Americans are affected by Alzheimer’s disease (AD), and up to 13 million will be affected by 2050. At present, there is no preventive or curative treatment for AD or in age-related cognitive decline and clinical trials of cognitive-modifying compounds have not succeeded in identifying an effective treatment. Despite a lot of efforts, no candidates are available to slow down the development or even cure this devastating disease. Although most of the efforts are focusing on the amyloid and the tau pathways, we have taken a different approach and targeted oxidative stress. Oxidative stress is a major pathogenic mechanism that underlies both the pre-clinical development and subsequent progression of AD, and one that could potentially be targeted preventively as well as therapeutically. Levels of reactive oxygen species (ROS) increase during inflammation, mitochondrial dysfunction, and metal redox cycling catalyzed by A, all processes associated with AD development. ROS-catalyzed lipid peroxidation generates bifunctional electrophiles (BFEs). We have shown that BFEs generated by oxidative stress accelerate Aß oligomerization, generating oligomers that have similar neurotoxicity and immunoreactivity as the amyloid-derived diffusible ligands. They inhibit proteosomal activity, cause mitochondrial dysfunction, and promote dendritic cell activation of T cells. Importantly, we have shown that levels of BFE adducts on proteins are significantly elevated in hippocampus of AD post mortem human brains, and correlate positively with both the CERAD plaque score and the Braak stage. We have found that 2-hydroxybenzylamine (2-HOBA) reacts 1,600-fold faster with BFEs than lysine, preventing protein modification in vitro and in vivo. Importantly, in hApoE4 transgenic mice, 2-HOBA inhibits all the effects of BFEs described above, and prevents working memory deficit. 2-HOBA, a natural product present in buckwheat seeds, has been developed for use in humans by Metabolic Technologies, Inc. (MTI, Ames, IA). The chemical, manufacturing and control data have been generated and pre-clinical pharmacology and toxicology data are currently being collected. In this project, we propose to do single and multiple escalation dose studies necessary to characterize pharmacokinetics, metabolism, and safety of 2-HOBA. We also propose to establish brain penetrance of 2-HOBA and to determine whether it reduces blood and CSF markers of oxidative modification of proteins.

大约有520万美国人受阿尔茨海默氏病（AD）的影响，最多13个百万将受到2050年的影响。目前，AD或在与年龄有关的认知下降和认知改良化合物的临床试验中成功地确定了有效的治疗方法。尽管付出了很多努力，但没有候选人可用于减慢发展，甚至治愈这种毁灭性疾病。虽然大部分努力的重点是淀粉样蛋白和tau途径，我们采取了不同的方法和靶向氧化应激。氧化应激是一种主要的致病机制，它是临床前的基础 AD的开发和随后的进展，并且有可能针对的预防性和治疗。活性氧（ROS）的水平增加炎症，线粒体功能障碍和由A催化的金属氧化还原循环，所有过程与广告开发相关。 ROS催化的脂质过氧化产生双功能电力（BFE）。我们已经表明，氧化应激加速Aß产生的BFE 寡聚，产生具有类似神经毒性和免疫反应性的低聚物淀粉样蛋白衍生的扩散配体。它们抑制蛋白质体活性，引起线粒体功能障碍并促进T细胞的树突状细胞激活。重要的是，我们已经表明蛋白质上的BFE加合物的水平在AD Mortem的海马中显着升高人的大脑，并与Cerad斑块得分和Braak阶段正相关。我们发现2-羟基苯胺（2-Hoba）反应于BFE的速度快1,600倍而不是赖氨酸，可预防体外和体内蛋白质修饰。重要的是，在hapoe4中转基因小鼠，2-HOBA抑制上述BFE的所有影响，并防止工作记忆不足。 2-HOBA是荞麦种子中存在的一种天然产品，已开发用于代谢技术公司的人类（MTI，AMES，IA）。化学，制造和对照数据已经生成，临床前药理学和毒理学数据是目前正在收集。在这个项目中，我们建议进行单一和多升级剂量表征2-HOBA的药代动力学，代谢和安全性所必需的研究。我们还建议建立2-HOBA的大脑渗透性，并确定其是否减少蛋白质氧化修饰的血液和CSF标记。