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: 10546238
• 负责人: RAJA G KHALIFAH
• 金额: $ 125.9万
• 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/10546238
• 关键词: 3xTg-AD mouse; Advanced Glycosylation End Products; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Antioxidants; Autopsy; Binding; Brain; Canis familiaris; Catalysis; Central Nervous System Agents; Clinical; Collaborations; Complex; Copper; Cornea; Data; Dementia; Diabetic Neuropathies; Disease; Disease Progression; Drug Kinetics; Exhibits; Free Radicals; Functional disorder; Glucose; Goals; Health system; Human; Impaired cognition; Intervention; Ions; Iron; Lead; Learning; Link; Maillard Reaction; Mediating; Memory impairment; Metabolism; Metals; Modeling; Mus; N(6)-carboxymethyllysine; Nerve; Nerve Degeneration; Neuraxis; Neurons; Neuropathy; Onset of illness; Oral; Oxidation-Reduction; Pathogenicity; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Population; Post-Translational Protein Processing; Pre-Clinical Model; Preparation; Process; Property; Proteins; Public Health; Reactive Oxygen Species; Rodent; Safety; Senile Plaques; Small Business Technology Transfer Research; Sodium Chloride; Structure; Therapeutic; Therapeutic Agents; Tissues; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Virulence Factors; adduct; amino group; ascorbate; base; chemical reaction; clinically relevant; diabetic; diabetic rat; drug candidate; early detection biomarkers; efficacy testing; glycation; human old age (65+); hyperphosphorylated tau; in vivo; inhibitor; meetings; mild cognitive impairment; mouse model; mutant; neuron loss; novel; novel marker; novel therapeutics; overexpression; oxidation; pre-clinical; presenilin; prevent; programs; safety assessment; safety study; screening; screening panel; tau Proteins; tau mutation; therapeutically effective; translation to humans

PROJECT SUMMARY Alzheimer’s Disease (AD) is recognized as a major public health issue that is 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. AGE formation is an established pathogenic factor in AD progression, impacting putative pathogenic mechanisms involving both amyloid beta and tau. Brains are replete with glucose and ascorbate, both of which fuel AGE formation. AGE formation is also 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 free radicals and reactive oxygen species (ROS) that are independently causative of 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 excellent binding of redox metal ions, particularly Cu2+. We recently 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. We plan to achieve our goals through two specific aims: (1) Test the efficacy of PTG-630 against central nervous system (CNS) dysfunction in an intervention paradigm; and (2) complete safety assessments of PTG-630 tri-HCl and initiate PK and safety studies in dog in preparation for pre-IND requirements. To mirror the most likely clinical use as an AD/ADRD therapeutic, we will start treatment with PTG-630 only when CNS dysfunctions are established. Studies will be performed using a suite of established mouse models of AD, namely mice overexpressing a) human non-mutant tau (htau), b) a mutant form of APP (Tg2567) or c) a triple transgenic (3xTg) model overexpressing mutant APP, mutant tau and mutant presenilin. We will also evaluate the ability of PTG-630 to reverse established loss of corneal nerves in the mouse models of AD, exploring whether corneal neuropathy can serve as a novel biomarker for early AD that will predict efficacy of intervention against CNS dysfunction. For Specific Aim 2, we will carry out non-GLP studies through pharmacokinetics, metabolism, and pharm-tox screening. We will also initiate dog safety and pharmacology studies. Praetego’s Amadorin PTG-630 is expected to offer a disease modifying breakthrough against AD/ADRD. Successful completion of this project will establish efficacy in reversing ADRD and provide sufficient experimental data to support a pre-IND FDA meeting towards therapeutic translation to humans.

项目摘要 阿尔茨海默氏病（AD）被认为是一个主要的公共卫生问题，预计在老龄化中会更糟 美国人口 - 到2050年，美国65岁及以上的人数将达到8800万。 尽管努力了大量努力，但缺乏足够有效的治疗选择。年龄形成是 在AD进展中建立的致病因素，影响了涉及的推定的致病机制 淀粉样蛋白β和Tau。大脑被葡萄糖和抗坏血酸植物取代，这两种燃料年龄形成。年龄 形成也是需要氧化还原金属离子催化的氧化物化学反应，众所周知AD 进展会导致促氧化铜和铁的大脑积累。这些年龄加速会产生免费 自由基和活性氧（ROS）独立于神经元损伤。我们的 假设是：（1）是脑渗透剂，（2）抑制年龄的形成，（3）减少 氧化还原金属离子氧化将在处理AD/ADRD方面具有效率。我们在这本小说中进步 “ Amadorin”候选药物PTG-630，这是一种潜在的高级糖基化末端产品（年龄）的抑制剂，也具有 双重电位作为抗氧化剂，由于其出色的氧化还原金属离子（尤其是Cu2+）的结合。我们最近 发现PTG-630可防止糖尿病大鼠和转基因小鼠模型中的轻度认知障碍 在疾病发作开始治疗时的AD。我们现在建议评估 PTG-630在反向建立的AD动物模型中的认知功能障碍和神经变性， 因为这是治疗剂临床使用的最可能方案。我们计划通过 两个具体目的：（1）测试PTG-630对中枢神经系统（CNS）功能障碍的效率 干预范式； （2）PTG-630 TRI-HCL的完整安全评估并启动PK和安全性 研究狗以准备预先要求。反映最可能的临床用途作为广告/ADRD 治疗性，只有在发生CNS功能障碍时，我们才能开始使用PTG-630治疗。研究将是 使用AD的既定小鼠模型进行的套件，即过表达的小鼠 tau（htau），b）App的突变形式（TG2567）或c）过表达突变体应用程序的三重转基因（3XTG）模型 突变的tau和突变体呈现。我们还将评估PTG-630扭转确定的损失的能力 AD小鼠模型中的角膜神经，探索角膜神经病是否可以作为新颖 早期AD的生物标志物将预测针对CNS功能障碍的干预效率。对于特定目标2，我们 将通过药代动力学，代谢和药物-TOX筛查进行非GLP研究。我们也会 启动狗安全和药理学研究。 Praetego的Amadorin PTG-630有望提供疾病 修改与AD/ADRD的突破。成功完成该项目将确立 逆转ADRD并提供足够的实验数据，以支持预先印度FDA的治疗会议 转化为人类。