A recent study conducted by researchers at the Wilmer Eye Institute, Johns Hopkins Medicine, sheds light on why certain patients with wet age-related macular degeneration (often referred to as “wet” AMD) do not experience improved vision with existing treatments. Additionally, the study explores how an experimental drug might be effectively combined with current treatments to preserve vision.
Wet AMD is one of the two types of age-related macular degeneration and is a progressive eye disorder characterized by the excessive growth of blood vessels in the retina, the light-sensitive layer of tissue at the back of the eye responsible for sending visual information to the brain. This abnormal blood vessel growth is driven by an overproduction of a protein called VEGF, which causes these blood vessels to leak fluid or bleed, leading to damage in the retina and subsequent vision loss.
Despite the significant vision impairment that many individuals with wet AMD face, less than half of those receiving monthly eye injections of anti-VEGF therapies experience substantial improvements in vision. Moreover, those who do initially benefit often find their vision worsening again over time.
A new report published in the week of November 4 in the Proceedings of the National Academy of Sciences explains how these anti-VEGF treatments might inadvertently hinder vision improvements by triggering the overproduction of another protein called ANGPTL4. Similar to VEGF, ANGPTL4 can also promote the excessive formation of abnormal blood vessels in the retina.
“We have previously noted that ANGPTL4 levels were heightened in patients who did not show favorable responses to anti-VEGF treatments,” states Akrit Sodhi, M.D., Ph.D., who is the corresponding author and an associate professor of ophthalmology at the Johns Hopkins University School of Medicine and the Wilmer Eye Institute. “Our findings indicate a surprising increase in ANGPTL4 levels in patients who received anti-VEGF injections, suggesting that the treatment itself activates this protein.”
The research team analyzed the levels of VEGF and ANGPTL4 in the eye fluid of 52 wet AMD patients undergoing different phases of anti-VEGF treatment. Before receiving anti-VEGF injections, the patients exhibited elevated levels of both ANGPTL4 and VEGF. After treatment, the VEGF levels predictably dropped, while ANGPTL4 levels increased, suggesting that ANGPTL4 remained active even after anti-VEGF injections, and that these treatments may have led to the rise in ANGPTL4. This ongoing activation of ANGPTL4 can contribute to the overproduction of blood vessels and insufficient vision improvement.
The researchers next sought to find a solution for the increased ANGPTL4 levels observed following anti-VEGF treatments by testing an experimental drug called 32-134D in mice with wet AMD. This drug targets a third protein, HIF-1, known for playing a role in wet AMD and diabetic eye disease due to its influence on VEGF production. The scientists believed that the HIF inhibitor 32-134D would similarly impact ANGPTL4 levels after anti-VEGF treatment since HIF-1 also stimulates ANGPTL4 production.
Mice treated with 32-134D exhibited reduced levels of HIF-1 and VEGF, along with lower ANGPTL4 levels and decreased blood vessel overgrowth. The findings in these mice were consistent with observations in human patients: even though VEGF levels were diminished with anti-VEGF treatments, ANGPTL4 levels increased, which blocked the effectiveness of these treatments in preventing blood vessel growth (and subsequent vision loss). The researchers discovered that combining 32-134D with anti-VEGF treatments stopped the rise in HIF-1, VEGF, and ANGPTL4 levels, and this combination proved to be more effective than either treatment alone, indicating a promising avenue for managing wet AMD.
“This research reveals a potential method to enhance anti-VEGF therapies for all patients, particularly benefiting those with wet AMD who continue to experience vision loss over time despite treatment,” Sodhi remarks. “We aim to advance three key objectives regarding wet AMD: to maximize the efficacy of current therapies, to identify new treatment options, and to work towards preventing the onset of wet AMD.”
Other contributors to the study include Deepti Sharma, Evan Lau, Yu Qin, Murilo Rodrigues, Chuanyu Guo, Emma McIntyre, Shaima Salman, Yousang Hwang, and Gregg L. Semenza from the Johns Hopkins University School of Medicine; Aumreetam Dinabandhu and Silvia Montaner from the University of Maryland; and Ala Moshiri from the University of California Davis. Aumreetam Dinabandhu and Yu Qin also have ties to the Johns Hopkins University School of Medicine and the Eye Hospital of China Medical University, respectively.
This research received support from multiple NIH grants including R01EY029750, R01EY032104, and EY001765 (the Wilmer Core Grant for Vision Research, Microscopy and Imaging Core Module); the TEDCO Maryland Innovation Initiative; the Research to Prevent Blindness, Inc., Special Scholar Award; the Sybil B. Harrington Stein Innovation Award; and unrestricted funding to the Wilmer Eye Institute, Johns Hopkins School of Medicine. Additional backing came from the Armstrong Family Foundation; the C. Michael Armstrong Professorship; and funding from the Armstrong Family Foundation; and the Branna and Irving Sisenwein Professorship in Ophthalmology. None of the funding organizations influenced the research design or execution. Akrit Sodhi and Gregg L. Semenza co-founded HIF Therapeutics, Inc., and hold equity in the company. Shaima Salman, Yousang Hwang, Akrit Sodhi, and Gregg L. Semenza are listed inventors on a provisional patent application PCT/US2022/039883, which has been examined and approved by Johns Hopkins University under its conflict of interest policies.
