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

摘要 阿尔茨海默病(AD)是美国第六大死亡原因，影响着500万人，但这 适应症缺乏有效的治疗方法。学术表现现场的首席合作调查员已经开发出 一种新型的双过氧体增殖物激活受体δ/γ激动剂OL-003 (之前为AU9)。第一阶段SBIR项目表明，OL-003减少了与AD相关的病理， 包括淀粉样蛋白堆积、tau磷酸化和神经炎症，以及改善胰岛素信号转导， 神经可塑性和行为缺陷，而在3xTg-AD小鼠中没有心脏或肝脏毒性。这个 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。这个 公司已经从我们的学术合作伙伴那里获得了OL-003的专利授权。 在这项第二阶段应用中概述的研究旨在测试另外两个动物模型和 评估GLP和非GLP研究中的药理学和毒理学。如果成功，此信息将定位 OL-003，用于其他IND使能研究(特别是CMC)，以提交IND申请并开始第一个在 人体临床试验。提出了三个目标。在目标1中，将使用TE4小鼠模型进行研究 在APOE4的情况下，测试OL-003对tau驱动的神经病理的有效性 晚发性AD的遗传危险因素。研究将包括测量OL-003对磷酸化tau的影响 水平，神经胶质增生和神经变性。在目标2中，OL-003对葡萄糖利用、线粒体 将研究小鼠大脑的功能和神经代谢。目前的研究支持这一假说 阿尔茨海默病的进展是由能量失调、线粒体缺陷和脑胰岛素抵抗以及 5xFAD模型适用于这些研究。在目标3中，在普洛斯条件下进行的研究将确定 OL-003在急性和6个月重复剂量毒性研究以及遗传毒性和致癌性研究中是否安全 学习。毒物动力学分析以及神经学、心血管和肺参数将 已评估。其他体外研究将涉及药物-药物相互作用的可能性，包括对药物的影响 转运蛋白活性和表达，以及靶向选择性分析，针对脱靶核受体和 代谢物鉴定。在这个项目成功完成后，该公司将拥有一个数据包 支持IND的研究应该对许可交易或与制药公司的合作伙伴具有吸引力 公司。

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.