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: 10701764
• 负责人: JAMES CARDELLI
• 金额: $ 80.58万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701764
• 关键词: 3xTg-AD mouse; Acute; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Behavior; Behavioral; Binding; Biological Assay; Biotechnology; 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; Genes; Gliosis; Glucose; Heart; Hepatotoxicity; Human; In Vitro; Inflammation; Insulin; Insulin Resistance; Late Onset Alzheimer Disease; Lead; Legal patent; Licensing; Link; Lipids; Lung; Marketing; Measures; Memory; Memory impairment; Metabolic; Metabolism; Mitochondria; Modeling; Molecular Conformation; Mus; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neurologic; Neuronal Plasticity; Nuclear Receptors; Oral; PPAR delta; Pathologic; Pathology; Pathway interactions; 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; Spinal nerve structure; Synaptic plasticity; Tauopathies; Testing; Thiazolidinediones; Toxic effect; Toxicokinetics; Toxicology; United States; Universities; Weight Gain; abeta accumulation; apolipoprotein E-4; blood-brain barrier crossing; blood-brain barrier permeabilization; carcinogenicity; commercialization; cytokine; delta receptors; design; effectiveness testing; efficacy study; efficacy testing; falls; first-in-human; genetic risk factor; genotoxicity; glucose metabolism; glucose uptake; human disease; improved; in silico; in vivo; 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; rosiglitazone; side effect; tau Proteins; 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.

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