# Small Molecule PPAR-alpha Agonism as a Novel Approach to Treat Eye Vascular Diseases

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA · 2020 · $288,515

## Abstract

Project Summary. Diabetic retinopathy (DR) is a common complication of diabetes and is the leading cause of
blindness in the working population. Currently, >40% of the patient population fails to respond to gold-standard
anti-VEGF direct intraocular injection treatments. New therapies that are superior to or synergistic with current
approaches are of great value to patients. Unlike current treatment options, new approaches should be non-
invasive (into the eye), affordable, and not reliant on specialized facilities. Our research program seeks to
develop small molecule PPARα agonists as first-in-class treatments for DR. The promise of PPARα agonism as
a novel strategy for treating DR has been confirmed in human clinical trials, wherein Fenofibrate (Feno), a
clinically used drug for hyperlipidemia, exhibited robust protective effects against DR and retinal
neovascularization (NV) in type 2 diabetic patients. We have determined that the protective effects of Feno are
unrelated to its lipid-lowering activity, but rather result from its agonism of PPARα. Feno however, suffers from
poor retinal distribution, low affinity/selectivity for PPARα, and chemotype related dose-limiting toxicities, all of
which will limit its use as a DR therapy. Recently, we have identified a novel class of non-fibrate PPARα agonists
that demonstrate improved potency and selectivity over Feno in vitro and exhibit efficacy in a retinal vascular
leakage DR animal model (i.p. administration). All totaled, these data provide proof-of-concept and clearly
demonstrate that 1) PPARα maintains critical roles in the major clinical features of DR and 2) Non-fibrate related
PPARα agonists with improved physicochemical properties and ocular distribution have high promise to become
first-in-class therapeutic options for DR. Specific Aims. (1) Structure-based hit to lead optimization of novel
PPARα agonists; (2) Determine the potency and efficacy of newly designed and synthesized analogs; (3) Define
the downstream molecular mechanism(s) underlying the protective effects of PPARα agonism against oxidative
stress and inflammation in DR. Study Design. We will leverage in silico PPARα models developed in our lab to
guide the design of improved agonists. Synthesized analogs will be assessed in in vitro biochemical and cellular
assays for PPARα potency, level of agonism, and isoform selectivity. Compounds meeting pre-defined metrics
will be advanced to secondary assays to determine anti-angiogenic, anti-oxidative, and neuroprotective effects
in vitro. Top compounds will be assessed for efficacy against retinal leukostasis, endothelial impairment, pericyte
loss, vascular leakage, visual function, and neuroretinal apoptosis in animal models. Top performing compounds
will be utilized for detailed studies to define the downstream molecular mechanisms underlying the protective
effects of PPARα agonism against the major etiological drivers of DR. The research is significant in that it will
provide new ...

## Key facts

- **NIH application ID:** 9971863
- **Project number:** 1R01EY030472-01A1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** Adam Scott Duerfeldt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $288,515
- **Award type:** 1
- **Project period:** 2020-05-01 → 2020-12-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971863

## Citation

> US National Institutes of Health, RePORTER application 9971863, Small Molecule PPAR-alpha Agonism as a Novel Approach to Treat Eye Vascular Diseases (1R01EY030472-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971863. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*