Researchers offer insights into wet AMD: Study reveals potential to enhance anti-VEGF therapy with experimental drug to preserve vision

An artist’s rendition of a choroidal neovascular lesion in a choroidal flat mount demonstrating expression of the transcription factor, hypoxia-inducible factor (HIF)-1⍺ (red) in RPE cells (green) in mouse eyes treated with aflibercept. (Image credit: Isabella Sodhi, McDonogh School)

A new study from researchers at the Wilmer Eye Institute, Johns Hopkins Medicine, reveals why some patients with wet age-related macular degeneration (wet AMD) fail to experience vision improvement with current treatments and how an experimental drug could enhance existing wet AMD therapies to preserve vision.

Wet AMD, one of two types of AMD, is a progressive eye condition resulting from an overgrowth of blood vessels in the retina.

Despite the severe vision loss often associated with wet AMD, fewer than half of the patients treated with monthly anti-VEGF injections experience significant vision improvements. Among those who do benefit, most eventually lose these gains over time.

Now, in a report published in Proceedings of the National Academy of Sciences, the Wilmer-led research team explains how anti-VEGF therapies might contribute to the lack of vision improvement by triggering the overexpression of a second protein, ANGPTL4. Like VEGF, ANGPTL4 can stimulate excessive production of abnormal blood vessels in the retina.¹

“We previously reported that ANGPTL4 increased in patients who did not respond well to anti-VEGF treatment,”said Akrit Sodhi, MD, PhD, corresponding author and associate professor of ophthalmology and the Branna and Irving Sisenwein Professor of Ophthalmology at Johns Hopkins University School of Medicine and the Wilmer Eye Institute. “In this paper, we observed a paradoxical rise in ANGPTL4 in patients who received anti-VEGF injections—the therapy itself activated this protein’s expression.”

The researchers compared VEGF and ANGPTL4 levels in the eye fluid of 52 wet AMD patients at different stages of anti-VEGF treatment. Before anti-VEGF injections, these patients exhibited high levels of both ANGPTL4 and VEGF proteins. After treatment, VEGF levels predictably declined, but ANGPTL4 levels rose, indicating that ANGPTL4 remained active and increased following anti-VEGF injections. This ANGPTL4 activity may lead to blood vessel overgrowth and prevent vision improvement.

The team then explored a solution for patients with increased ANGPTL4 following anti-VEGF treatment by testing the experimental drug 32-134D in mice with wet AMD. This drug reduces levels of HIF-1, a protein involved in wet AMD and diabetic eye disease due to its role in activating VEGF production. Researchers theorized that the HIF-inhibitor 32-134D might similarly reduce ANGPTL4 after anti-VEGF treatment, as ANGPTL4 production is also regulated by HIF-1.

In mice treated with 32-134D, the team observed decreases in HIF-1, VEGF, ANGPTL4, and blood vessel overgrowth. Mice treated solely with anti-VEGF therapies confirmed the team’s findings in human patients: although VEGF levels dropped, ANGPTL4 levels increased, which inhibited the anti-VEGF therapies’ effectiveness in reducing blood vessel growth and vision loss. Combining 32-134D with anti-VEGF treatments prevented increases in HIF-1, VEGF, and ANGPTL4. This combination therapy was more effective than either drug alone, suggesting promise for enhanced wet AMD treatment.¹

“This work provides a way to improve anti-VEGF therapy for all patients and may help a subset of wet AMD patients who lose vision over time despite treatment,” Sodhi concluded. “We hope this research will advance our three goals related to wet AMD: maximizing the efficacy of current therapies, identifying new treatments, and preventing wet AMD altogether.”

Additional study authors include Deepti Sharma, Evan Lau, Yu Qin, Murilo Rodrigues, Chuanyu Guo, Emma McIntyre, Shaima Salman, Yousang Hwang, and Gregg L. Semenza of Johns Hopkins University School of Medicine; Aumreetam Dinabandhu and Silvia Montaner of the University of Maryland; and Ala Moshiri of the University of California, Davis. Dinabandhu and Qin are also affiliated with Johns Hopkins University School of Medicine and the Eye Hospital of China Medical University, respectively.

This research was supported by National Institutes of Health grants R01EY029750, R01EY032104, and EY001765 (the Wilmer Core Grant for Vision Research, Microscopy, and Imaging Core Module); the TEDCO Maryland Innovation Initiative; Research to Prevent Blindness, Inc.; the Sybil B. Harrington Stein Innovation Award; an unrestricted grant to the Wilmer Eye Institute, Johns Hopkins School of Medicine; the Armstrong Family Foundation; the C. Michael Armstrong Professorship; and the Branna and Irving Sisenwein Professorship in Ophthalmology. The funding organizations had no role in designing or conducting the study.

Akrit Sodhi and Gregg L. Semenza are co-founders of and hold equity in HIF Therapeutics, Inc. Shaima Salman, Yousang Hwang, Akrit Sodhi, and Gregg L. Semenza are inventors on a provisional patent application, PCT/US2022/039883. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies.

Reference

1. D. Sharma, E. Lau, Y. Qin, K. Jee, M. Rodrigues, C. Guo, A.Dinabandhu, E. McIntyre, S. Salman, Y. Hwang, A. Moshiri, G.L.Semenza, S. Montaner, A. Sodhi, VEGF inhibition increases expression of HIF-regulated angiogenic genes by the RPE limiting the response of wet AMD eyes to aflibercept, Proc. Natl. Acad. Sci. U.S.A. 121 (46) e2322759121. Published November 4, 2024. Accessed November 5, 2024. https://doi.org/10.1073/pnas.2322759121 (2024).