June 15, 2015

Protein Involved in Diabetic Eye Disease

At a Glance

  • Researchers identified a protein involved in an advanced stage of diabetic retinopathy, a diabetic eye disease that threatens vision.
  • The discovery may help explain why current treatments don’t help all patients and suggests a novel approach for research into therapies.
Retinal Blood Vessels. In patients with proliferative diabetic retinopathy, retinal blood vessels (white) become damaged, leading to areas without blood flow (black) and others with leaky, abnormal vessels (bright white).Wilmer Photography, Wilmer Eye Institute, Johns Hopkins School of Medicine

More than 40% of Americans with diabetes develop diabetic retinopathy. It’s the most common cause of vision loss among working-age Americans. The disease is caused by damage to blood vessels in the retina. This restricts the oxygen supply and triggers the growth of new blood vessels, a process called angiogenesis. However, these new blood vessels are extremely fragile and often leak fluid or bleed, causing vision loss and sometimes blindness.

Advanced diabetic retinopathy, or proliferative diabetic retinopathy, is treated by using a laser to seal leaky blood vessels and slow the growth of new ones. But this treatment can reduce peripheral, night, and color vision and isn’t always permanent. Patients may also receive drugs that inhibit vascular endothelial growth factor (VEGF), a protein that stimulates angiogenesis. However, anti-VEGF therapy may only temporarily stop the disease and carries its own risks. Some patients don’t respond at all to the therapy, suggesting that other factors may be involved.

A group of researchers led by Dr. Akrit Sodhi of the Johns Hopkins University School of Medicine investigated other factors that might drive angiogenesis in proliferative diabetic retinopathy. Their work, which was funded by NIH’s National Eye Institute (NEI), was published on June 9, 2015, in Proceedings of the National Academy of Sciences.

The researchers first compared VEGF levels in aqueous fluid from the eyes of healthy people and from patients with diabetes with and without proliferative diabetic retinopathy. While most of the patients had much more VEGF in their aqueous fluid, some had levels that were below the average for the healthy controls. The low-VEGF fluid from these patients, however, triggered as much angiogenesis in lab-grown cells as high-VEGF fluid. In fact, anti-VEGF therapy didn’t affect the ability of aqueous fluid from patients to trigger angiogenesis, despite low levels of the protein. These findings confirmed that another compound must contribute to the process.

By restricting oxygen flow to retinal cells, the team went on to discover a protein called angiopoietin-like 4 that, like VEGF, is present at much higher levels in the oxygen-deprived cells. The protein was also present at high levels in low-VEGF aqueous fluid from the eyes of patients who had recently received anti-VEGF therapy. Boosting levels of angiopoietin-like 4 greatly increased angiogenesis. In laboratory experiments, decreasing production of angiopoietin-like 4 or blocking its action reduced angiogenesis. Most importantly, inhibiting both VEGF and angiopoietin-like 4 reduced angiogenesis more than targeting just one of the proteins.

“Anti-VEGF therapies have been very effective, but not for 100% of patients,” Sodhi says. “What we suggest is perhaps this other factor, angiopoeitin-like 4, may play an important role in diabetic eye disease and potentially other eye diseases as well.”

These results suggest that a drug that could block the action of angiopoietin-like 4 might help prevent proliferative diabetic retinopathy, particularly if combined with VEGF. Meanwhile, the protein might prove useful for predicting which diabetic retinopathy patients will respond to anti-VEGF therapy.

—by Brandon Levy

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Reference: Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande M, Daoud Y, Solomon S, Wenick A, Lutty GA, Semenza GL, Montaner S, Sodhi A. Proc Natl Acad Sci USA. 2015 Jun 9;112(23):E3030-9. doi: 10.1073/pnas.1423765112. Epub 2015 May 26. PMID: 26039997.

Funding: NIH’s National Eye Institute (NEI); Research to Prevent Blindness Foundation; and William and Ella Owens Medical Research Foundation.