# Bifunctional Inhibitors of STING as Chemical Probes for Diabetic Retinopathy

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2024 · $228,009

## Abstract

PROJECT SUMMARY
More than 40% of patients with diabetic retinopathy (DR) are refractory to direct intraocular injection of anti-
VEGF antibodies, the standard of care. The inability to effectively treat DR puts a heavy burden on the health
care system and limits the quality of life for those affected. The need for novel, clinically relevant targets that can
be exploited for new therapies is very clear. Diabetes is well-known to induce retinal mitochondrial dysfunction
that leads to DNA damage and cytosolic release. Cytosolic DNA activates the cGAS-STING pathway, inducing
inflammation. Although the cGAS-STING signaling axis is essential for sensing foreign DNA and thus
contributing to innate immunity, aberrant activation of this pathway by self-DNA is a significant contributor to
autoinflammatory and autoimmune diseases. Activation of cGAS-STING due to chronic diabetes-induced
inflammation leads to activation of circulating monocytes, eventually giving rise to leukostasis. Leukostasis
causes cell death and breakdown of the blood-retinal barrier, leading to retinal vascular leakage, a major cause
of diabetic macular edema and leading cause of vision loss in diabetic patients. We have shown that 1) the
cGAS-STING pathway is activated in ischemic retinopathy; 2) inhibition of STING attenuates monocyte activation
and alleviates retinal leukostasis and angiogenesis; 3) STING knockout significantly reduces retinal leakage,
number of leukocytes in the retina, and DR relevant inflammatory factors in an oxygen-induced retinopathy
murine model; and 4) small molecule agonism of peroxisome proliferator-activated receptor alpha (PPARa)
inhibits the cGAS-STING signaling axis and cytosolic mitochondrial DNA release. The objective of this
exploratory R21 proposal is to assess two mechanistically differentiated approaches to inhibit STING with
bifunctional small molecules in the context of DR. In Aim 1 we will assess small molecule induced STING
degradation through proteolysis-targeting chimeras (PROTACs) as a strategy for STING inhibition in the context
of DR. The PROTAC strategy is unexplored in the eye but especially well-suited for ocular conditions. In Aim 2
we will leverage our success in developing selective PPARa agonists as new therapeutic leads for DR to develop
first-in-class bifunctional probes that simultaneously agonize PPARa (neuronal protection) and inhibit STING
(retinal vascular homeostasis and inflammation) to explore the potential benefits of polypharmacology in retinal
disease. The heterobifunctional modulators of these two targets are expected to provide a spatiotemporal benefit
affecting multiple cell types and pathological events. This work is conceptually and technically innovative and is
expected to provide the fundamental data needed to enable proof-of-concept for the PROTAC and multi-action
compound strategies in ocular contexts (new approaches), a foundation for targeting STING in DR and related
retinal diseases (new target), and new c...

## Key facts

- **NIH application ID:** 10993227
- **Project number:** 1R21EY035454-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Adam Scott Duerfeldt
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,009
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993227

## Citation

> US National Institutes of Health, RePORTER application 10993227, Bifunctional Inhibitors of STING as Chemical Probes for Diabetic Retinopathy (1R21EY035454-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10993227. Licensed CC0.

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