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.

项目总结 阿尔茨海默病(AD)被认为是一个主要的公共健康问题，预计随着老龄化的加剧 美国人口-到2050年，美国65岁及以上人口的数量将达到8800万。然而， 尽管进行了密集的努力，但仍然缺乏足够有效的治疗选择。年龄形成是一种 确定了AD进展中的致病因素，影响了两者可能的致病机制 淀粉样蛋白β和tau。大脑中充满了葡萄糖和抗坏血酸，这两种物质都促进了年龄的形成。年龄 形成也是一种需要氧化还原金属离子催化的氧化化学反应，众所周知AD 进展会导致大脑中促氧化剂铜和铁的积累。这些老化促进剂会产生 自由基和活性氧物种(ROS)是神经元损伤的独立原因。我们的 假设一种候选药物：(1)是脑穿透性的，(2)抑制AGE形成，(3)减少 氧化还原金属离子氧化治疗AD/ADRD疗效显著。我们在这项提议中提出了小说 “Amadorin”候选药物PTG-630，一种有效的晚期糖基化终产物(AGEs)抑制剂，也有 作为抗氧化剂的双重潜力，因为它与氧化还原金属离子，特别是Cu2+有很好的结合。我们最近 发现PTG-630在糖尿病大鼠和转基因小鼠模型中预防轻度认知障碍 在疾病发作时开始治疗的阿尔茨海默病。我们现在建议评估这种药物的治疗潜力 PTG-630逆转多种AD动物模型已建立的认知功能障碍和神经退行性变， 因为这是临床使用治疗剂的最有可能的情况。我们计划通过以下方式实现我们的目标 两个具体目标：(1)检测PTG-630对小鼠中枢神经系统(CNS)功能障碍的疗效 干预模式；(2)完成PTG-630三氯化氢的安全性评估，启动PK和安全性 在犬身上的研究，为IND前的要求做准备。将最有可能的临床应用映射为AD/ADRD 治疗方面，只有在中枢神经系统功能障碍确定后，我们才会开始使用PTG-630进行治疗。研究将会是 使用一套已建立的阿尔茨海默病小鼠模型，即过量表达a)人类非突变的小鼠 Tau(Htau)，b)APP的突变形式(Tg2567)或c)过表达突变APP的三重转基因(3xTg)模型， 突变的tau和突变的早老素。我们还将评估PTG-630扭转既定损失的能力 角膜神经在小鼠AD模型中的作用，探讨角膜神经病是否可以作为一种新的 早期AD的生物标志物将预测干预对中枢神经系统功能障碍的疗效。对于特定的目标2，我们 将通过药代动力学、代谢和药毒筛查进行非GLP研究。我们还将 启动狗的安全和药理学研究。Praetego的Amadorin PTG-630有望提供一种疾病 针对AD/ADRD的修改突破。这一项目的成功完成将在 逆转ADRD并提供足够的实验数据支持IND前FDA会议 翻译成人类。