UVA research provides new insight into common causes of vision loss

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UVA Health scientists have discovered an unknown contributor to harmful blood vessel growth in the eye that could lead to new treatments for blinding macular degeneration and other common causes of vision loss.

UVA's Jayakrishna Ambati, MD, and Shao-bin Wang, PhD, and their colleagues have identified a new target to prevent the formation of abnormal tangles of blood vessels associated with eye conditions such as neovascular age-related macular degeneration, proliferative diabetic retinopathy and ischemic retinal vein occlusion.

Our study has opened up the possibility of mitigating aberrant blood vessel growth in eye diseases by targeting the epigenetic machinery. Through local targeting of the epigenetic regulator, we have gained a deeper understanding of how ocular immune cells can cause a loss of control over blood vessel growth under the retina. This approach also offers a new direction for the development of more effective, cost-efficient and accessible interventions, thereby avoiding issues such as drug resistance, which is a growing concern with conventional anti-VEGF therapies used in clinical treatments."

Jayakrishna Ambati, founding director of UVA's Center for Advanced Vision Science and member of the University of Virginia School of Medicine's Department of Ophthalmology

Understanding vision loss

Scientists have known that abnormal vessel overgrowth in the eye is fueled by excessive amounts of a substance called "vascular endothelial growth factor-A," or VEGF, that plays an important role in blood vessel formation. There are now treatments available that target VEGF to prevent vessel overgrowth, and they often provide dramatic benefits at first. Unfortunately, these benefits can fade with time. That leaves doctors in need of better treatments to help preserve patients' eyesight.

Ambati and Wang's new research identifies a key protein that determines VEGF levels. Blocking this protein in lab mice reduced their VEGF levels significantly, and it did so in a targeted way, without unwanted side effects. The scientists noted, for example, that they observed no toxic effects on the retina, the light-sensing portion of the eye where the vessel overgrowth occurs. "This fat mass and obesity-associated (FTO) protein was previously shown to be correlated with obesity in humans. Unexpectedly, we found it also play important roles in regulating ocular neovascularization through an epigenetic mechanism," Ambati said. "This exciting discovery finally answers a longstanding question about how ocular immune cells, such as macrophages, contribute to abnormal blood vessel growth under the retina. This question was first investigated by our team 20 years ago, and we're thrilled to have found an answer."

In addition to identifying a promising target for the development of new treatments for vision loss, the discovery sheds important light on the fundamental mechanisms responsible for the blood vessel overgrowth that robs millions of people of their sight. Neurovascular age-related macular degeneration alone affects more than 200 million people worldwide. While much more research and testing will be needed before the new finding could be translated into a treatment, the UVA scientists are excited about the potential of the discovery.

"Current strategies for treating ocular neovascular disorders, which primarily focus on regulating the protein levels of VEGF, are not perfect. Therefore, it is imperative to identify more targetable candidates to develop alternative therapies," Wang said. "We are hopeful that our study will pave the way for the development of new treatments, ultimately reducing the burden of neovascular-related illnesses."

Findings published

The researchers have published their findings in the scientific journal Signal Transduction & Targeted Therapy. The research team consisted of Shao-bin Wang, Yosuke Nagasaka, Dionne Argyle, Ayami Nagasaka, Praveen Yerramothu, Bradley D. Gelfand and Ambati. Ambati is a co-founder of DiceRx, iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics and has done consulting work unrelated to the research. A full list of the authors' disclosures is included in the paper.

The research was supported by the National Institutes of Health, grants R01EY028027, R01EY029799, R01EY031039 and R01AG082108; the UVA Strategic Investment Fund; the DuPont Guerry III professorship; a gift from Mr. and Mrs. Eli W. Tullis; the Annette Lightner Fund; BrightFocus Foundation Award M2020114; and the Owens Family Foundation.

Source:
Journal reference:

Wang, S-b., et al. (2023) Targeting the m6A mRNA demethylase FTO suppresses vascular endothelial growth factor release and choroidal neovascularization. Signal Transduction and Targeted Therapy. doi.org/10.1038/s41392-022-01277-4.

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