Researchers funded in part by the National Eye Institute (NEI) have 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.

Diabetic retinopathy is the most common cause of vision loss among working-age Americans. More than 40 percent of Americans with diabetes develop the disease, which 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. Also, some patients don’t respond to the therapy, suggesting there may be factors other than VEGF that drive angiogenesis.

A group of researchers led by Dr. Akrit Sodhi of the Johns Hopkins University School of Medicine investigated such factors in a recent study published in Proceedings of the National Academy of Sciences. Their analysis began with samples of eye fluid donated by people who had undergone eye surgery. Working with lab-grown blood vessel cells, they found evidence for potent angiogenesis factors, other than VEGF, in eye fluid from people with proliferative diabetic retinopathy. One of these factors was a protein called angiopoietin-like 4.

Further experiments on the lab-grown human cells revealed that blocking the action of both VEGF and angiopoietin-like 4 markedly reduced blood vessel growth.

“This is an exciting article as it may explains why a certain population with proliferative diabetic retinopathy is non-responsive to anti-VEGF treatment,” said Neeraj Agarwal, Ph.D., a program director in the NEI Division of Extramural Research. “This certainly opens a new target(s) for possible drug discovery. Also, it may be useful to measure the levels of angiopoietin-like 4 protein before deciding to treat proliferative diabetic retinopathy with anti-VEGF therapy.”

Read more in NIH Research Matters, and in the press release from Johns Hopkins Medicine.

NEI (grants EY021189 and EY001765), Research to Prevent Blindness, and the William and Ella Owens Medical Research Foundation provided funding for this research.

Reference: Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Babapoor-Farrokhran S et al. Proc Natl Acad Sci USA. June 2015 doi: 10.1073/pnas.1423765112.