Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)

Amadorins 用于改善阿尔茨海默病和相关痴呆症 (ADRD)

• 批准号: 10819236
• 负责人: RAJA G KHALIFAH
• 金额: $ 5万
• 依托单位: PRAETEGO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10819236
• 关键词: Advanced Glycosylation End Products; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Antioxidants; Binding; Brain; Catalysis; Clinical; Copper; Dementia; Disease; Disease Progression; Economic Burden; Exhibits; Free Radicals; Glucose; Health system; Impaired cognition; Ions; Iron; Metals; Nerve Degeneration; Neurons; Onset of illness; Oxidation-Reduction; Patients; Persons; Pharmaceutical Preparations; Population; Proteins; Public Health; Reactive Oxygen Species; Therapeutic; Therapeutic Agents; Transgenic Mice; Virulence Factors; adduct; ascorbate; chemical reaction; diabetic rat; drug candidate; human old age (65+); inhibitor; mild cognitive impairment; novel; novel therapeutics; oxidation; pre-clinical; prevent; tau Proteins; therapeutically effective

PROJECT SUMMARY Alzheimer’s Disease (AD) and related dementias (ADRD) are recognized as major public health issues that are projected to worsen in the aging U.S. population — the number of people of age 65 and older in the U.S. will reach 88 million by 2050. However, despite intensive efforts, there is an absence of sufficiently effective therapeutic options. Advanced glycation end products (AGE) formation is an established pathogenic factor in AD progression, impacting both amyloid beta and tau. Brains are replete with glucose and ascorbate, both of which are AGE precursors. AGE formation is initiated by the breakdown of glucose adducts on proteins via an oxidative chemical reaction requiring redox metal ion catalysis, and it is known that AD progression leads to brain accumulation of pro-oxidant copper and iron. These AGE accelerants generate toxic free radicals and reactive oxygen species (ROS) that can independently cause neuronal damage. Our hypothesis is that a drug candidate that: (1) is brain penetrant, (2) inhibits AGE formation, and (3) reduces oxidation by redox metal ions will exhibit efficacy in treating AD/ADRD. We advance in this proposal the novel “Amadorin” drug candidate PTG-630, a potent inhibitor of advanced glycation end products (AGEs) that also has the dual potential as an antioxidant due to its binding of redox metal ions, particularly Cu2+. We previously discovered that PTG-630 prevents mild cognitive impairment in diabetic rats and in a transgenic mouse model of AD when treatment was begun at onset of disease. We now propose to evaluate the therapeutic potential of PTG-630 in reversing established cognitive dysfunction and neurodegeneration in multiple animal models of AD, as this is the most likely scenario for clinical use of a therapeutic agent.

项目摘要 阿尔茨海默氏病（AD）和相关痴呆症（ADRD）被认为是主要的公共卫生问题 预计在美国老龄化的人口中会恶化 - 美国65岁及以上的人数将 到2050年达到8800万。但是，尽管进行了密集的努力，但缺乏有效的有效性 治疗选择。 进度，淀粉样蛋白β和tau都充满了葡萄糖和肌肉 年龄形成是通过氧化剂上蛋白质上的葡萄糖成瘾者的分解来引发的 需要氧化还原金属离子catalsysy的化学反应 促氧化铜和铁的积累。 可以独立引起神经元损害的氧气（ROS）。 那是：（1）是脑穿透力，（2）抑制年龄的形成，（3）通过氧化还原金属离子降低氧化 在此提案中，我们提高了“ Amadorin”候选药物PTG-630的功效 高级糖基化最终产品（年龄）的有效抑制剂，该抑制剂也具有双重氧化剂 氧化还原金属离子的结合，尤其是Cu2+。 糖尿病大鼠的认知障碍和AD的转基因小鼠模型开始，当 疾病。我们现在建议评估逆转认知 多种AD动物模型中的功能障碍和神经变性，是临床最有可能的情况。 使用治疗剂。