Recent research has discovered a protein that plays a key role in diabetes-related vision loss, which may lead to better treatments for a major cause of blindness and might also have implications for other diseases, including cancer.
In a report published in the Journal of Clinical Investigation, researchers at the University of Utah in Salt Lake City describe what they found about the protein, which is known as ADP-ribosylation factor 6 (ARF6), and its role in diabetic retinopathy.
They report how blocking ARF6 could be a way to reduce diabetic retinopathy, a sight-damaging disease that people with diabetes can develop as a result of chronic high blood sugar. They also describe a compound that showed this effect in rodent models of the disease.
“What is exciting about this study,” explains co-first author Weiquan Zhu, Ph.D., who is a research assistant professor in internal medicine, “is that we and our collaborators identified a compound (NAV-2729) that inhibits ARF6, which is crucial for the development of diabetic retinopathy.”
Diabetic retinopathy is a disease that damages the blood vessels in the retina, which is the light-sensitive tissue at the back of the eye that enables sight. The damage is the result of high blood sugar, and, as it progresses, it distorts the blood vessels, causing them to leak and impair vision.
When the disease enters the advanced stages, new abnormal blood vessels also start to grow in the retina, adding to the damage. Eventually, there is permanent scarring that leads to severe vision impairment and blindness.
The worldwide burden of diabetes-related vision loss is growing at an alarming pace.
In the United States, estimates suggest that there will be 19.4 million people aged 40 and over with diabetic retinopathy and vision-threatening diabetic retinopathy in 2050 — three times the number in 2005.
The new study has uncovered the role that ARF6 plays in the control of vascular endothelial growth factor (VEGF), a signaling protein that plays a key role in the development of diabetic retinopathy.
There is a treatment for diabetic eye disease in which patients receive a monthly injection of anti-VEGF drugs directly into the eye. But the treatment, which reduces inflammation, only works for around 40 percent of patients.
ARF6 appears to increase and maintain a receptor for VEGF, helping to unleash a series of events — including inflammatory signals — that leads to eye disease.
“ARF6 acts like a traffic cop at a busy intersection within a cell,” explains senior author Dr. Dean Li, formerly of the University of Utah and now head of translational medicine at Merck & Co. “ARF6 orchestrates multiple inflammatory signals that contribute to inflammation common in many diseases, including diabetic eye disease.”
The team also identified two other proteins, called ARNO and GEP100, that help to maintain the signals by activating ARF6 at two different cell locations.
When ARNO activates ARF6, it ferries the VEGF receptor into the cell, allowing its signal to be amplified. When GEP100 activates the protein, it causes it to ferry it back to outside the cell, effectively “recycling” it for reuse in a new signaling cycle.
The researchers suggest that their discoveries identify a signaling cycle that promotes two features of diabetic retinopathy: increased blood vessel leakage and the birth of new, weaker blood vessels.
They found that injecting NAV-2729 into the eyes of rodents that had been treated to develop diabetic retinopathy significantly reduced both features of the diabetic eye disease.
Further work now needs to be done to determine the long-term effects of the treatment and establish whether or not it is safe and effective in humans.
“We think these results are important because they identified a mechanism by which ARF6 controls VEGF receptor signaling and therefore may have much broader implications, extending to other diseases that involve VEGF receptor activation, such as cancer.”
Prof. Shannon Odelberg, University of Utah Health