Alzheimers disease (AD) is the sixth leading cause of death in United States, yet this indication lacks truly effective therapeutics to mitigate this disease. To address this problem, a novel (partial) peroxisomal proliferator activatinggamma (PPAR?) nuclear receptor agonist (AU-9) that has selective amino acid interactions in the receptor ligand-binding domain was developed. Preliminary data suggest AU-9 may reduce AD-related pathologies, including amyloid accumulation, neuro-inflammation, behavioral deficits and neurodegeneration (reduced neuronal plasticity). The goal of this current application is to further test and develop AU-9 in preparation to submit an IND application to the FDA to initiate clinical trials. Two aims are proposed to achieve this goal. Aim 1 will evaluate the effective concentration, absorption and distribution of AU-9 in rodent models of Alzheimers disease. The minimal concentration of AU-9 needed to improve neuronal plasticity will be determined by electrophysiological analysis. Maximum tolerated doses will also be assessed. Live-cell in vitro imaging will be used to validate preliminary data, support in vivo findings proposed herein and gain mechanistic insight to AU-9 effects. Finally, pharmacokinetic analysis and tissue distribution of AU-9 using LC-MS analysis will be performed in a dose and time dependent manner. Aim 2 will evaluate the safety of AU- 9 following long-term treatment in mice. Current full PPAR? agonists produce unwanted side effects on the heart and liver. Potential adverse reactions of AU-9 will be observed (testing over a range of doses over 6 months) on both the heart and liver, organs normally adversely impacted with current clinical PPAR? agonists. In addition, this aim will focus on key IND enabling data required by FDA guidelines, including measuring the effects of AU-9 on liver enzyme levels (CYP enzymes). The results of these studies are expected to confirm AU-9 as a potential treatment or preventive therapy for AD and ultimately support efforts to submit an IND application and initiate Phase I clinical trials testing AU-9.
Public Health Relevance Statement: NARRATIVE Alzheimers disease (AD) and AD related dementias (ADRD) constitute a major public health problem and have been reported to triple healthcare costs. Preliminary studies show that a partial PPAR? agonist, AU-9, demonstrates promising effects against AD. The proposed project will determine the optimal dose of AU-9 for safety and efficacy in an AD mouse model and will position this compound as a potential preventive and/or treatment for AD and ADRD.
Project Terms: 3xTg-AD mouse; absorption; Address; Adverse effects; Adverse reactions; aging population; Agonist; Alzheimer's Disease; Alzheimer's disease model; Alzheimer's disease related dementia; Amino Acids; Amyloid; animal data; Anti-inflammatory; base; Behavioral; Biological Availability; Biological Markers; Biotechnology; Blood - brain barrier anatomy; Brain; Cardiovascular system; care costs; Cause of Death; Cells; Chronic; Clinical; clinical application; Clinical Trials; clinically relevant; Cognition; Computer Simulation; Data; Dementia; design; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Edema; efficacy study; Electrophysiology (science); Enzymes; Evaluation; Future; Gene Expression; Goals; Guidelines; Health Care Costs; Heart; Heart failure; heart function; Hepatocyte; Hepatotoxicity; Human; human disease; Image; improved; In Vitro; in vivo; Incidence; indexing; Individual; innovation; insight; insulin sensitizing drugs; intraperitoneal; intravenous administration; Legal patent; Ligand Binding Domain; Link; Liver; Malignant neoplasm of urinary bladder; Maximum Tolerated Dose; Measures; Memory impairment; molecular targeted therapies; mouse model; Mus; Nerve Degeneration; neuroinflammation; Neuronal Plasticity; neurotropin; novel; Nuclear Receptors; off-patent; Oral; Organ; Outcome; Pathologic; Pathology; Patients; Permeability; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pioglitazone; Positioning Attribute; pre-clinical; Preparation; Prevention; Preventive; Preventive therapy; Privatization; promoter; Property; Public Health; receptor; Regimen; Reporting; Research; research and development; Rodent Model; rosiglitazone; Route; Safety; Sales; Schedule; Scientist; side effect; Small Business Innovation Research Grant; tau Proteins; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Thiazolidinediones; Time; Treatment Cost; treatment effect; Treatment Efficacy; Ultrasonography; United States; Universities; Xenobiotics
