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。

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' 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

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.

项目摘要 阿尔茨海默病（AD）是痴呆症的主要原因，全世界每85名成年人中就有1人受到影响。缺乏 改善疾病的疗法或可靠地监测治疗的机械生物标志物是关键的未满足的需求。 目前的护理标准（SoC），即，乙酰胆碱酯酶或NMDA受体阻滞剂，提供有限的 救济金目前的证据表明，在AD中，通过氧化应激， 应激（OxS）、线粒体（mt）功能障碍和炎症。这种病理性三重奏发生在早期， AD的基础。OxS主要由非生产性线粒体呼吸引起，并促进线粒体功能障碍。 氧化鸟嘌呤（8-oxo-dG）是最重要的氧化和致突变性DNA损伤，特别是在mtDNA中。 过量意味着修复不足。通过增强线粒体DNA修复来改善线粒体功能将改变AD 进展8-oxo-dG的修复是一种不可或缺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， 缺失和片段化，并最终导致生物能量能力和细胞活力的丧失， 病理特征片段化的mtDNA被排出以刺激多种促炎途径。虽然 有可能用于AD治疗的MT方法，目前没有靶向基础的治疗方法， 氧化损伤的切除修复。Luciole Pharmaceuticals的方法是使用小分子来改善DNA修复 分子以增强DNA糖基化酶OGG 1的催化活性。在碱基切除的第一步 修复时，OGG 1切除8-氧代-dG，同时招募其他途径酶来完成细胞核中的修复， 线粒体增加OGG 1活性将导致有效去除8-氧代-dG以防止链断裂。 最终，能量和炎症将改善以保护神经元功能并减缓AD进展。 最近在AD小鼠模型中使用物理或药理方法的出版物支持我们的观点 假说.在我们之前成功发现新型OGG 1激活剂（OAA）的基础上，我们将开发 与AD SoC药物不同的“一流”口服小分子OAA，可改善AD， 在数十亿美元的市场中提高患者的生活质量。在第一阶段SBIR项目中，我们计划 OAA化学和体外筛选测定以改善OAA效力和体内功效。如果成功，我们 第二阶段项目将包括：1）推进候选人选择，2）测试优化的化合物， 激发的人源iPSC和鼠AD模型中的mtDNA排出，3）早期安全性评估和 4)产生用于测试候选化合物的新型突变小鼠模型。