Current treatments sometimes fail to help people with “wet” age-related macular degeneration — and researchers now think they know why.

Wet AMD is caused by an overgrowth of blood vessels in the retina, the light-sensing tissue at the back of the eye. The vessels leak fluid or bleed, damaging the retina and causing vision loss.

To combat this, doctors prescribe medications that slow the growth of new blood vessels, called anti-VEGF (vascular endothelial growth factor) drugs.

Unfortunately, these anti-VEGF drugs might actually hamper vision improvements by triggering the over-expression of a second blood-vessel-related protein, researchers have discovered.

This second protein, ANGPTL4, also can stimulate overproduction of abnormal blood vessels in the retina, researchers reported Nov. 4 in the Proceedings of the National Academy of Sciences.

These findings could explain why fewer than half of patients who receive monthly anti-VEGF eye injections wind up showing any major improvements in their vision, researchers said.

“We have previously reported that ANGPTL4 was increased in patients who did not respond well to anti-VEGF treatment,” said researcher Dr. Akrit Sodhi, an associate professor of ophthalmology at the Johns Hopkins University School of Medicine, in Baltimore.

“What we saw in this paper was a paradoxical increase of ANGPTL4 in patients that received anti-VEGF injections — the anti-VEGF therapy itself turned on expression of this protein,” Sodhi said in a Hopkins news release.

For the study, researchers compared VEGF and ANGPTL4 levels in the eye fluid of 52 patients with wet AMD, all of whom were receiving anti-VEGF treatments.

After anti-VEGF treatment, their VEGF levels decreased but their ANGPTL4 levels rose. Such ANGPTL4 activity could promote more damaging blood vessel overgrowth, researchers said.

The team then investigated ways to limit ANGPTL4 levels, using an experimental drug on mice with wet AMD.

The drug decreases levels of a third protein, HIF-4, known to be involved in wet AMD by promoting VEGF production.

The drug also decreased VEGF and ANGPTL4 levels in mice, and limited overgrowth of blood vessels, researchers found.

Combining the experimental drug with existing anti-VEGF meds proved more effective than either drug alone in mice, results showed.

“This work exposes a way to improve anti-VEGF therapy for all patients and potentially help a subset of patients with wet AMD who still lose vision over time despite treatment,” Sodhi said. “Our hope is that this [project] will further the three goals we have related to wet AMD: make current therapies as effective as possible, identify new therapies and prevent people from ever getting wet AMD."