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)

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默氏病（AD）被认为是一个重大的公共卫生问题，预计会随着老龄化而恶化美国人口——到 2050 年，美国 65 岁及以上的人口数量将达到 8800 万。但是，尽管付出了巨大的努力，但目前仍缺乏足够有效的治疗方案。 AD 进展中确定的致病因素，影响涉及两者的假定致病机制 β 淀粉样蛋白和 tau 蛋白富含葡萄糖和抗坏血酸，这两种物质都会促进 AGE 的形成。形成也是一种氧化化学反应，需要氧化还原金属离子催化，已知AD 进展导致大脑中促氧化铜和铁的积累，这些 AGE 加速剂产生游离。自由基和活性氧（ROS）独立引起神经元损伤。假设候选药物：(1) 具有脑渗透性，(2) 抑制 AGE 形成，以及 (3) 氧化还原金属离子的氧化将在治疗 AD/ADRD 中发挥功效，我们在此提案中提出了新颖的观点。 “Amadorin”候选药物 PTG-630，一种有效的晚期糖基化终末产物 (AGE) 抑制剂，还具有由于其与氧化还原金属离子（特别是 Cu2+）的出色结合，因此具有作为抗氧化剂的双重潜力。发现 PTG-630 可预防糖尿病大鼠和转基因小鼠模型的轻度认知障碍我们现在建议评估 AD 的治疗潜力。 PTG-630 可逆转多种 AD 动物模型中已建立的认知功能障碍和神经变性，因为这是治疗剂临床使用最有可能的情况，我们计划通过以下方式实现我们的目标。两个具体目标：(1) 测试 PTG-630 对中枢神经系统 (CNS) 功能障碍的功效干预范式；(2) 完成 PTG-630 tri-HCl 的安全性评估并启动 PK 和安全性在狗身上进行的研究，为 IND 前的要求做准备，以反映最可能的临床用途作为 AD/ADRD。治疗方面，只有在中枢神经系统功能障碍研究确定后，我们才会开始使用 PTG-630 进行治疗。使用一套已建立的 AD 小鼠模型进行，即过度表达 a) 人类非突变体的小鼠 tau (htau)，b) APP (Tg2567) 的突变形式或 c) 过表达突变 APP 的三重转基因 (3xTg) 模型，我们还将评估 PTG-630 逆转已确定的 tau 蛋白和早老素缺失的能力。 AD小鼠模型中的角膜神经，探索角膜神经病变是否可以作为一种新的治疗方法早期 AD 的生物标志物将预测针对 CNS 功能障碍的干预效果。对于特定目标 2，我们。我们还将通过药代动力学、代谢和药物毒性筛选开展非 GLP 研究。启动狗的安全性和药理学研究 Praetego 的 Amadorin PTG-630 有望提供一种疾病。该项目的成功完成将确立针对 AD/ADRD 的突破性进展。扭转 ADRD 并提供足够的实验数据来支持 IND 前 FDA 会议以实现治疗翻译给人类。