Second blood-vessel-growth protein implicated in PDR

Targeting the blood-vessel-growth protein angiopoietin-like 4 (ANGPTL4) along with anti-vascular endothelial growth factor (VEGF) therapy could increase the effectiveness of treatments for the prevention of proliferative diabetic retinopathy (PDR), according to researchers at The Johns Hopkins University and the University of Maryland. A summary of their study appeared online in Proceedings of the National Academy of Sciences.

Diabetic retinopathy is the most common cause of vision loss in working-age adults in the United States. According to the National Eye Institute, 40 to 45% of Americans with diabetes have diabetic retinopathy.

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Laser-sealing eye blood vessels can save central vision, but can also sacrifice peripheral and night vision, according to Akrit Sodhi, MD, Ph.D., an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine. Several recently developed drugs - bevacizumab, ranibizumab and aflibercept - work by blocking the action of VEGF, a growth factor released as part of a chain of signals in response to low oxygen levels, which stimulates the growth of new, often abnormal, blood vessels. But studies have shown that although these drugs slow progression to PDR, they do not always reliably prevent it. In addition, the anti-VEGF therapies have shown some success delaying the development of PDR, but they don’t work for all patients.

Reporting on a study with lab-grown human cells, researchers say that blocking a second blood vessel growth protein - ANGPTL4  -together with VEGF could increase the effectiveness of the treatment for these patients.

The researchers tested levels of VEGF in samples of fluid from the eye taken from healthy people, people with diabetes who did not have diabetic retinopathy, and people with diabetic retinopathy of varying severity. 

Next: Results

While levels of VEGF tended to be higher in those with proliferative diabetic retinopathy, some of their fluid had less VEGF than did that of the healthy participants. But even the low-VEGF fluid from patients with proliferative diabetic retinopathy stimulated blood vessel growth in lab-grown cells. 

“The results suggested to us that although VEFG clearly plays an important role in blood vessel growth, it’s not the only factor,” Dr. Sodhi said.

A series of experiments in lab-grown human cells and mice revealed that when the researchers blocked the action of both VEGF and ANGPTL4 in fluid from the eyes of people with proliferative diabetic retinopathy, it markedly reduced blood vessel growth in lab-grown cells. 

If a drug can be found that safely blocks the second protein’s action in patients’ eyes, it might be combined with the anti-VEGF drugs to prevent many cases of proliferative diabetic retinopathy, Dr. Sodhi suggested.

The team is now investigating whether ANGPTL4 might also play a role in other eye diseases, such as macular degeneration, which destroys the central portion of the retina.

The researchers said that although they cannot rule out a contribution from other angiogenic factors in the promotion of retinal neovascularization in patients with PDR, the results from this study suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR. Accordingly, the next step should be the development of anti-ANGPTL4 therapies. They noted that this will require the identification of the relevant endothelial cell receptor through which ANGPTL4 mediates its pathological effects in the retina.

The researchers added that this study demonstrated that aqueous fluid levels of ANGPTL4 correlate very well with the levels of ANGPTL4 in the vitreous, which suggests that ANGPTL4 levels in the aqueous fluid could serve as a diagnostic biomarker to help predict the level of diabetic eye disease in vulnerable populations.

Next: "Relatively straightforward"

“Acquiring aqueous fluid from patients is relatively straightforward and poses limited risks on patients, and although there is considerable overlap of VEGF levels in aqueous fluid of control patients, diabetic patients without diabetic retinopathy, and diabetics with no-proliferative diabetic retinopathy or PDR, ANGPTL4 levels were strongly predictive of the presence or absence of PDR,” the researchers wrote.

“Although therapies targeting the potent angiogenic mediator vascular endothelial growth factor have been remarkably successful for the treatment of diabetic macular edema, this approach has not proven sufficient to prevent the development of retinal neovascularization, implicating additional angiogenic factor(s) in PDR pathogenesis,” the researchers concluded. “We demonstrate here that angiopoietin-like 4 is a potent angiogenic mediator with markedly increased expression in the eyes of PDR patients. Our studies identify a novel therapeutic target for the treatment of ocular neovascular disease and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis.”