Researchers identify a key protein in Diabetic Retinopathy

Researchers at University of Utah Health have identified a protein, ADP-ribosylation factor 6 (ARF6), which is crucial for the development of diabetic retinopathy. Published in The Journal of Clinical Investigation, they identified a compound, NAV-2729, which inhibits or blocks ARF6, reducing the chances of development of diabetic retinopathy.

Studies were conducted in animals treated to simulate the diabetic condition. By injecting NAV-2729 into the eyes of these animals, vessel leakage, as well as, the overgrowth of blood vessels, another driver of disease, were significantly reduced.

The long-term efficacy of treatment remains unknown. It also remains to be determined whether the drug will be suitable as a therapeutic intervention for people.

As per Dean Li, Ph.D., Vice President, Head of Translational Medicine, Merck & Co. and senior author on the paper, who was Associate Vice President and Chief Scientific Officer at Univ of Utah Health and co-Founder of Navigen Inc., ARF6 orchestrates multiple inflammatory signals that contribute to inflammation common in many diseases, including diabetic eye disease.

ARF6 amplifies and maintains the signal protein (vascular endothelial growth factor (VEGF)) receptor, which stimulates a series of cascading responses, leading to a diseased state in the eye.

Currently, patients with diabetic eye disease usually receive monthly or bimonthly anti-VEGF injections directly into the eye to reduce inflammation, a treatment that is successful in only 40 to 50 percent of patients. In this study, injections of NAV-2729 into the eyes of diabetic mice were more effective in reducing blood vessel leakage than the anti-VEGF injections.

Also new to this study, the researchers identified two proteins — GEP100 and ARNO — that play a critical role in the signaling process. These proteins activate ARF6 at two different locations in the cell to continue the signaling cycle.

According to Shannon Odelberg, Ph.D., Research Associate Professor in Internal Medicine at Univ of Utah Health and corresponding author on the study, ARNO activates ARF6, which shuttles the VEGF receptor into the cell where its signal can be amplified. GEP100 activates ARF6 to recycle the VEGF receptor back to the outside of the cell where it can be reactivated for the signaling process to begin again.  This signaling loop triggers disease by increasing blood vessel leak and the formation of new and weak blood vessels.

The team of researchers plan to continue to explore the role of ARF6 in other inflammatory diseases.

This work received funds from the National Institutes of Health, Juvenile Diabetes Research Foundation, American Asthma Foundation and the Burroughs Wellcome Fund.

Acknowledgements: Univ of Utah Health News; photo credit: M. Elizabeth Hartnett, M.D.

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