Discovery and development of OGG1 activators as precision drugs for modification of Alzheimer's disease progression.

发现和开发 OGG1 激活剂作为改变阿尔茨海默病进展的精准药物。

基本信息

批准号：
10759620
负责人：
WILLIAM L RUMSEY
金额：
$ 30.35万
依托单位：
LUCIOLE PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10759620
关键词：
APP-PS1 Acetylcholinesterase Adult Affect Allosteric Site Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid Base Excision Repairs Binding Bioenergetics Biological Biological Assay Biological Markers Brain Brain Diseases Cause of Death Cell Death Cell Death Induction Cell Nucleus Cell Survival Cells Cessation of life Chemistry Chronic Circulation Clinical Cognition Cognitive deficits Collaborations DNA DNA Repair DNA glycosylase DNA lesion Deacetylation Dementia Development Disease Disease Progression Disease model Down-Regulation Excision Exercise Failure Genetic Polymorphism Guanine Histone Deacetylase Human In Vitro Induced pluripotent stem cell derived neurons Inflammation Inflammatory Lead Lesion Libraries Life Expectancy Locomotion Machine Learning Marketing Measurement Mediating Medicine Memory impairment Metabolic Mexican Americans Mitochondria Mitochondrial DNA Monitor Motion Mus N-Methyl-D-Aspartate Receptors Neurons OGG1 gene Oral Oral Medicine Oxidative Stress Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Plasma Prefrontal Cortex Property Proteins Publications Publishing Quality Control Quality of life Reaction Reactive Oxygen Species Respiration Respiratory Chain Safety Small Business Innovation Research Grant Structure Testing Toxin Zebrafish age related blood-brain barrier penetration candidate selection clinical candidate cognitive function cost effective drug modification economic cost enzyme pathway improved in vivo in vivo evaluation induced pluripotent stem cell loss of function member meter mitochondrial dysfunction mouse model mutant mouse model neuroprotection new therapeutic target next generation novel novel therapeutic intervention overexpression oxidation oxidative damage pharmacologic pre-clinical precision drugs preclinical development preservation prevent recruit reduce symptoms repaired research clinical testing response safety assessment screening small molecule socioeconomics standard of care success targeted treatment tau Proteins transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a leading cause of dementia with 1 in 85 adults affected worldwide. The lack of disease-modifying therapies or mechanistic biomarkers to reliably monitor treatment are key unmet needs. Current standard of care (SoC), i.e., acetylcholinesterase or NMDA receptor blockade, provides limited symptom-relief. Current evidence indicates that an inter-related, mechanistic triad is formed in AD by oxidative stress (OxS), mitochondrial (mt) dysfunction and inflammation. This pathological trio occurs early and is fundamental to AD. OxS primarily arises from unproductive mt-respiration and promotes mt-dysfunction. Oxidized guanine (8-oxo-dG) is the most prominent oxidative and mutagenic DNA lesion, particularly in mtDNA. Excessive amounts signify insufficient repair. Improving mt-function by enhancing mtDNA repair will modify AD progression. Repair of 8-oxo-dG is an indispensable, mitochondrial quality control mechanism that largely occurs by base excision repair. Accumulation of 8-oxo-dG leads to double-stranded breaks which cause mtDNA deletions and fragmentation and culminates in loss of bioenergetic capacity and cell viability, a prominent AD pathological feature. Fragmented mtDNA is expulsed to stimulate multiple proinflammatory pathways. Although there are mt-approaches with potential for AD treatment, there are presently no therapies that target base excision repair of oxidative damage. Luciole Pharmaceuticals’ approach is to improve DNA repair using small molecules to enhance the catalytic activity of the DNA glycosylase, OGG1. In the first step of base excision repair, OGG1 excises 8-oxo-dG while recruiting other pathway enzymes to complete repair in the nucleus and mitochondria. Increasing OGG1 activity will result in the efficient removal of 8-oxo-dG to prevent strand breaks. Ultimately, energetics and inflammation will improve to preserve neuronal function and slow AD progression. Recent publications using either physio- or pharmacological approaches in AD murine models support our hypothesis. Building on our previous success in discovering novel OGG1 activators (OAAs), we will develop “first-in-class” orally available, small molecule OAAs that are differentiated from AD SoC drugs to modify AD and advance patient quality of life in a multi-billion-dollar market. In this Phase I SBIR project, we plan to progress OAA chemistry and in vitro screening assays to improve OAA potency and in vivo efficacy. If successful, our Phase II project will include; 1) advancing a lead to candidate selection, 2) testing optimized compounds for mtDNA expulsion in challenged human-derived iPSCs and murine AD models, 3) early safety assessment and 4) generating a novel mutant mouse model for testing the candidate compound.

项目概要阿尔茨海默病 (AD) 是导致痴呆症的主要原因，全世界每 85 名成年人中就有 1 人受到影响。疾病缓解疗法或可靠监测治疗的机械生物标志物是未满足的关键需求。当前的护理标准 (SoC)，即乙酰胆碱酯酶或 NMDA 受体阻断，提供的治疗效果有限目前的证据表明，AD 中通过氧化作用形成了一个相互关联的机械三联征。应激（OxS）、线粒体（mt）功能障碍和炎症这三个病理因素很早就发生，并且是很常见的。 OxS 是 AD 的基础，主要源自非生产性 mt 呼吸并促进 mt 功能障碍。氧化鸟嘌呤 (8-oxo-dG) 是最显着的氧化和诱变 DNA 损伤，特别是在线粒体 DNA 中。过量意味着修复不足通过增强 mtDNA 修复来改善 mt 功能将改变 AD。 8-oxo-dG 的修复是一种不可或缺的、大量发生的线粒体质量控制机制。通过碱基切除修复，8-oxo-dG 的积累导致双链断裂，从而导致 mtDNA。缺失和碎片，最终导致生物能能力和细胞活力的丧失，这是一种突出的AD 碎片化的线粒体DNA被排出以刺激多种促炎途径。存在具有治疗 AD 潜力的 mt 方法，但目前还没有针对碱基的疗法 Luciole Pharmaceuticals 的方法是利用小分子物质来改善 DNA 修复。分子增强 DNA 糖基化酶 OGG1 的催化活性，在碱基切除的第一步中。修复过程中，OGG1 切除 8-oxo-dG，同时招募其他途径酶来完成细胞核内的修复，增加 OGG1 活性将有效去除 8-oxo-dG，以防止链断裂。最终，能量和炎症将得到改善，以保持神经功能并减缓 AD 进展。最近在 AD 小鼠模型中使用生理或药理学方法的出版物支持我们的研究基于我们之前发现新型 OGG1 激活剂 (OAA) 的成功，我们将开发出假设。 “一流”的口服小分子 OAA，与 AD SoC 药物不同，可改变 AD 和在价值数十亿美元的先进市场中提高患者的生活质量在这一阶段的 SBIR 项目中，我们计划取得进展。 OAA 化学和体外筛选测定可提高 OAA 效力和体内功效如果成功，我们的。第二阶段项目将包括：1) 推进候选药物选择，2) 测试优化化合物受挑战的人源 iPSC 和小鼠 AD 模型中的 mtDNA 排出，3) 早期安全评估和 4) 生成用于测试候选化合物的新型突变小鼠模型。