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: 10704225
• 负责人: RAJA G KHALIFAH
• 金额: $ 124.61万
• 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/10704225
• 关键词: 3xTg-AD mouse; Acceleration; 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; Central Nervous System Agents; Clinical; Collaborations; Complex; Complications of Diabetes Mellitus; Copper; Cornea; Data; Dementia; Diabetic Neuropathies; Disease; Disease Progression; Drug Kinetics; Economic Burden; Exhibits; Free Radicals; Functional disorder; Glucose; Goals; Health system; Human; Impaired cognition; In Vitro; Intervention; Ions; Iron; Lead; Learning; Link; Maillard Reaction; Mediating; Memory impairment; Metabolism; Metals; Modeling; Mus; N(6)-carboxymethyllysine; Nerve; Nerve Degeneration; Neurofibrillary Tangles; 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; abeta accumulation; absorption; adduct; amino group; ascorbate; chemical reaction; clinically relevant; diabetic rat; drug candidate; early detection biomarkers; efficacy testing; glycation; human old age (65+); hyperphosphorylated tau; in vivo; inhibitor; mild cognitive impairment; mouse model; mutant; neuron loss; novel; novel marker; novel therapeutics; overexpression; oxidation; paired helical filament; pre-Investigational New Drug meeting; pre-clinical; presenilin; prevent; programs; safety assessment; safety study; screening; screening panel; tau Proteins; tau mutation; therapeutically effective; translation to humans; translational therapeutics

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 阿尔茨海默病（AD）被认为是一个主要的公共卫生问题，预计将在老龄化中恶化 美国人口-到2050年，美国65岁及以上的人口将达到8800万。然而，在这方面， 尽管作出了大量努力，但仍缺乏足够有效的治疗选择。年龄的形成是一个 确定了AD进展中的致病因素，影响了假定的致病机制， 淀粉样蛋白β和tau。大脑中充满了葡萄糖和抗坏血酸，这两者都促进了AGE的形成。年龄 形成也是需要氧化还原金属离子催化的氧化化学反应，并且已知AD 进展导致促氧化剂铜和铁的脑积累。这些AGE促进剂产生免费的 自由基和活性氧（ROS）是神经元损伤的独立原因。我们 假设候选药物：（1）是脑渗透剂，（2）抑制AGE形成和（3）降低 通过氧化还原金属离子的氧化将显示出治疗AD/ADRD的功效。我们在这个提议中提出， “Amadorin”候选药物PTG-630，一种有效的晚期糖基化终产物（AGEs）抑制剂， 由于其对氧化还原金属离子，特别是Cu 2+的优异结合，具有作为抗氧化剂的双重潜力。我们最近 发现PTG-630可以预防糖尿病大鼠和转基因小鼠模型的轻度认知障碍 在疾病发作时开始治疗的AD。我们现在建议评估 PTG-630在多种AD动物模型中逆转已建立的认知功能障碍和神经变性， 因为这是治疗剂临床应用的最可能的情况。我们计划通过以下方式实现我们的目标 两个具体目的：（1）测试PTG-630对中枢神经系统（CNS）功能障碍的功效， 干预范例;和（2）完成PTG-630 tri-HCl的安全性评估，并启动PK和安全性 为IND前要求做准备的犬研究。反映最可能作为AD/ADRD的临床用途 治疗，我们将开始治疗PTG-630只有当中枢神经系统功能障碍建立。研究将 使用一套已建立的AD小鼠模型进行，即过表达a）人非突变体的小鼠 tau（htau），B）APP的突变形式（Tg 2567）或c）过表达突变APP的三重转基因（3xTg）模型， 突变tau和突变早老素。我们还将评估PTG-630逆转已确立的细胞凋亡的能力。 角膜神经在AD小鼠模型，探讨是否角膜神经病变可以作为一种新的 早期AD的生物标志物，其将预测针对CNS功能障碍的干预的功效。对于具体目标2，我们 将通过药代动力学、代谢和药物毒性筛选进行非GLP研究。我们还将 启动犬安全性和药理学研究。Praetego的Amadorin PTG-630有望提供一种疾病 改变对AD/ADRD的突破。该项目的成功完成将在以下方面建立效力： 逆转ADRD，并提供足够的实验数据，以支持IND前FDA会议， 翻译给人类。