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

> **NIH NIH R42** · OLEOLIVE, INC. · 2022 · $1,692,440

## Abstract

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.

## Key facts

- **NIH application ID:** 10482506
- **Project number:** 2R42AG065069-03A1
- **Recipient organization:** OLEOLIVE, INC.
- **Principal Investigator:** JAMES CARDELLI
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,692,440
- **Award type:** 2
- **Project period:** 2019-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10482506

## Citation

> US National Institutes of Health, RePORTER application 10482506, Evaluation of a dual PPAR agonist for treatment of Alzheimer's disease (2R42AG065069-03A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10482506. Licensed CC0.

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