New findings from the Wilmer Eye Institute at Johns Hopkins Medicine provide insights into why some patients with the “wet” form of age-related macular degeneration (AMD) do not see improvement in their vision despite undergoing treatment. These findings also shed light on how an experimental drug could potentially enhance the effect of existing treatments for wet AMD, a condition that progresses due to excessive growth of blood vessels in the retina.
In wet AMD, an overabundance of a protein called VEGF prompts blood vessel growth in the eye’s retina, the light-sensitive tissue that sends visual signals to the brain. These new blood vessels then leak fluid or bleed, damaging the retina and causing vision loss. Even though wet AMD can lead to severe vision loss, less than half of patients who undergo regular eye injections, also known as anti-VEGF therapies, experience significant improvement in their sight. Moreover, the visual gains that some patients do experience often diminish over time.
Published in the Proceedings of the National Academy of Sciences, the report by the Wilmer-led research team reveals that these anti-VEGF treatments might actually be contributing to the lack of vision improvement. This is due to the overproduction of another protein called ANGPTL4, which, like VEGF, also stimulates the overproduction of abnormal blood vessels in the retina.
The research team discovered that levels of ANGPTL4 increased paradoxically in patients who received anti-VEGF injections. Prior to anti-VEGF treatment, patients with wet AMD had high levels of both ANGPTL4 and VEGF proteins. After treatment, while VEGF levels predictably decreased, levels of ANGPTL4 rose even higher. This indicates that ANGPTL4 remained active after the anti-VEGF injections, and the treatments indirectly led to an increase in ANGPTL4, which can promote blood vessel growth and prevent vision improvement.
To combat this issue, the researchers tested an experimental drug, 32-134D, on mice with wet AMD. This drug reduces the levels of a third protein, HIF-1, which is known to activate VEGF production and plays a role in wet AMD and diabetic eye disease. The researchers hypothesized that 32-134D might have a similar effect on ANGPTL4, since this protein’s production is also initiated by HIF-1.
In mice treated with 32-134D, the researchers observed reduced levels of HIF-1, VEGF, ANGPTL4, and blood vessel overgrowth. This supports the findings in human patients where anti-VEGF treatments alone resulted in lower VEGF levels but increased ANGPTL4 levels, thus impeding the full effectiveness of the anti-VEGF treatments in preventing blood vessel growth and vision loss. The researchers also found that combining 32-134D with anti-VEGF treatments effectively prevented the increase in HIF-1, VEGF, and ANGPTL4, making the treatment combination more effective than using either drug alone.
This study brings hope for improving anti-VEGF therapy for all patients and potentially helping those with wet AMD who continue to lose vision over time despite treatment. The researchers aim to make current therapies as effective as possible, identify new therapies, and prevent the onset of wet AMD.
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