Evaluation of a dual PPAR agonist for treatment of Alzheimer's disease

双 PPAR 激动剂治疗阿尔茨海默病的评价

• 批准号: 10482506
• 负责人: JAMES CARDELLI
• 金额: $ 169.24万
• 依托单位: OLEOLIVE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482506
• 关键词: 3xTg-AD mouse; Acute; Address; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Behavior; Behavioral; Binding; Biological Assay; Biotechnology; Blood - brain barrier anatomy; Brain; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Chemicals; Clinical; Clinical Trials; Cognition; Data; Defect; Diabetes Mellitus; Diabetic mouse; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Interactions; Drug Transport; Elderly; Evaluation; Exhibits; FDA approved; Family; Funding; Gliosis; Glucose; Growth Factor Gene; Heart; Hepatotoxicity; Human; In Vitro; Inflammation; Insulin Resistance; Late Onset Alzheimer Disease; Lead; Legal patent; Licensing; Link; Lipids; Lung; Measures; Memory; Memory impairment; Metabolic; Metabolism; Mitochondria; Modeling; Molecular Conformation; Mus; Nerve; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neurologic; Neuronal Plasticity; Nuclear Receptors; Oral; PPAR delta; Pathologic; Pathology; Pathway interactions; Patients; Peer Review; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Pioglitazone; Play; Positioning Attribute; Prevention; Privatization; Property; Public Health; Regulation; Reporting; Research; Research Personnel; Research Support; Role; Safety; Scientist; Small Business Innovation Research Grant; Synaptic plasticity; Tauopathies; Testing; Thiazolidinediones; Time; Toxic effect; Toxicokinetics; Toxicology; United States; Universities; Vertebral column; Weight Gain; abeta accumulation; blood-brain barrier permeabilization; carcinogenicity; commercialization; cytokine; delta receptors; design; effectiveness testing; efficacy study; efficacy testing; first-in-human; genetic risk factor; genotoxicity; glucose metabolism; glucose uptake; human disease; improved; in silico; in vivo; insulin sensitizing drugs; insulin signaling; lipid biosynthesis; lipid metabolism; liver function; member; mouse model; neuroinflammation; neuropathology; novel; novel therapeutics; oxidation; performance site; phase 1 study; pre-clinical; receptor; relating to nervous system; rosiglitazone; side effect; tau Proteins; tau phosphorylation; tau-1; therapeutic target; therapeutically effective

SUMMARY Alzheimer’s disease (AD) is the sixth leading cause of death in United States, affecting 5M people, yet this indication lacks effective therapeutics. The lead co-investigator at the academic performance site has developed a novel dual peroxisomal proliferator activating receptor delta/gamma (PPARδ/γ) agonist called OL-003 (previously AU9). The Phase I SBIR project demonstrated that OL-003 reduced AD-related pathologies, including amyloid accumulation, tau phosphorylation and neuroinflammation, and improved insulin signaling, neuronal plasticity and behavioral deficits, while exhibiting no heart or liver toxicity in 3xTg-AD mice. The company is a private preclinical biotechnology company developing novel therapies for mitigating AD. The company has in-licensed the patent for OL-003 from our academic partner. Studies outlined in this Phase II application are designed to test efficacy in two additional animal models and assess pharmacology and toxicology in GLP and non-GLP studies. If successful, this information will position OL-003 for additional IND-enabling studies (CMC in particular) to submit an IND application and begin first-in- human clinical trials. Three aims are proposed. In aim 1, research will be performed using the TE4 mouse model to test the effectiveness of OL-003 against tau-driven neuropathology in the context of APOE4, the strongest genetic risk factor for late-onset AD. Studies will include measuring the impact of OL-003 on phosphorylated tau levels, gliosis and neurodegeneration. In aim 2, the impact of OL-003 on glucose utilization, mitochondrial function and neurometabolism in the brains of mice will be studied. Current research supports the hypothesis that AD progression is driven by energy dysregulation, mitochondrial defects, and brain insulin resistance and the 5xFAD model is suitable for these studies. In aim 3, research performed under GLP conditions will determine if OL-003 is safe in acute and 6-month repeat dose toxicity studies as well as genotoxicity and carcinogenicity studies. Toxicokinetic analysis as well as neurologic, cardiovascular, and pulmonary parameters will be evaluated. Additional in vitro studies will address drug-drug interaction potential, including effects on drug transporter activity and expression, as well as target selectivity assays against off-target nuclear receptors and metabolite identification. Upon successful completion of this project, the company will possess a data package of IND-enabling research that should be attractive for a license deal or partnership with a pharmaceutical company.

总结 阿尔茨海默氏病（AD）是美国第六大死亡原因，影响500万人，但这 适应症缺乏有效的治疗方法。学术表现网站的首席合作研究员开发了 新型过氧化物酶体增殖物激活受体δ/γ双重激动剂OL-003 （以前的AU 9）。I期SBIR项目证明OL-003减少AD相关的病理， 包括淀粉样蛋白积累、tau磷酸化和神经炎症，以及改善的胰岛素信号传导， 神经可塑性和行为缺陷，而在3xTg-AD小鼠中没有表现出心脏或肝脏毒性。的 公司是一家私人临床前生物技术公司，开发缓解AD的新疗法。的 公司已经从我们的学术合作伙伴那里获得了OL-003的专利许可。 本II期申请中概述的研究旨在测试另外两种动物模型的疗效， 在GLP和非GLP研究中评估药理学和毒理学。如果成功，这些信息将定位 OL-003，用于其他IND使能研究（特别是CMC），以提交IND申请并开始首次入组 人体临床试验提出了三个目标。在目标1中，将使用TE 4小鼠模型进行研究 为了测试OL-003在APOE 4的情况下对tau驱动的神经病理学的有效性， 迟发性AD的遗传风险因素。研究将包括测量OL-003对磷酸化tau蛋白的影响 水平，神经胶质增生和神经变性。在目的2中，OL-003对葡萄糖利用、线粒体代谢和细胞内代谢的影响。 将研究小鼠脑中的功能和神经代谢。目前的研究支持这一假设 AD进展是由能量失调、线粒体缺陷和脑胰岛素抵抗驱动的， 5xFAD模型适用于这些研究。在目标3中，在GLP条件下进行的研究将确定 如果OL-003在急性和6个月重复给药毒性研究以及遗传毒性和致癌性中是安全的 问题研究将进行毒代动力学分析以及神经系统、心血管和肺参数 评估。其他体外研究将探讨药物间相互作用的可能性，包括对药物的影响。 转运蛋白活性和表达，以及针对脱靶核受体的靶向选择性测定， 代谢物鉴定成功完成该项目后，该公司将拥有一个数据包， 对许可协议或与制药公司合作具有吸引力的IND研究 公司