Seeing the bigger picture: Stunting abnormal blood vessel growth in the eyes

The more you think about the level of detail that goes into seeing –– from perceiving colors, shapes and movements to translating them into electrical signals for our brains to interpret –– the more you realize how much we take vision for granted. 

The human eye is one of our most elaborate organs. Not only is it operated by over two million working parts, but it can also process up to 36 thousand pieces of new information per hour. To fuel such complex processing, our retinas –– the structures in our eyes where light is converted into nerve impulses –– need to be constantly fed with oxygen and nutrients. 

According to Christopher Schafer, a postdoctoral researcher in Courtney Griffin’s lab at the Oklahoma Medical Research Foundation (OMRF), it is for that reason that vision requires a rich network of vessels. “The eye is in this perpetual balance of having enough blood vessels to meet its nutritional needs while at the same time not having so much that it actually blocks vision,” he explained. But when this balance is disrupted, sight can become impaired. If blood vessels start to grow excessively, some of them might end up where they are not supposed to be, which could give rise to neovascular diseases like diabetic retinopathy and complicate the conversion of light into visual nerve impulses. 

To understand how this damage to vision could be reverted, Schafer and his colleagues conducted a study, published on PNAS in October, investigating the potential of a class of transcription factors –– biological molecules that control how genes are transcribed into RNA, the code for making proteins –– to stunt this abnormal growth. 

In their experimental setup, they looked at a type of vasculature in the eye called hyaloid vessels. According to Schafer, these vessels are unique in that they are only around for a while, and do something that almost no other vessel does under regular circumstances: dissipate completely within a short amount of time.

In humans, this natural process occurs while the fetus is still in the uterus, but in mice, it happens right after birth, making murine models convenient to research hyaloid regression. “We thought maybe the hyaloid vessels could teach us something about how you could naturally cause vessel regression,” Schafer said. Since a number of diseases involving vessels in the retina are caused by overgrowth, understanding how hyaloids become naturally eliminated could provide a pathway to undo damage to vision.

Serendipity played a role in the team’s encounter of E-26 transformation-specific (ETS) transcription factors as a potential target. When they were looking at readouts for their study of hyaloid vessel regression in mouse models, the team noticed that two proteins, ETS-related gene (ERG) and Friend leukemia integration 1 (FLI1), were significantly suppressed in the lining of the vessels right before regression. “We happened to notice that ERG was very highly expressed in blood vessels that were not regressing and almost entirely absent in blood vessels that were,” Schafer explained. The group then hypothesized that forcing the downregulation of ERG and FLI1 could perhaps provoke blood vessel regression. 

To test this hypothesis, they utilized the YK-4-279 molecule –– an inhibitor that can block the biological activity of ERG and FLI1 and is commonly studied as a therapeutic agent against prostate cancer. This particular study, Schafer said, was the first to test YK-4-279 in the context of diseases that affect the eye.

To understand whether YK-4-279 could facilitate vessel regression in ocular diseases caused by vessel overgrowth, the team used mice as models of retinopathy. Then, they injected YK-4-279 into their vitreous –– a fluid that makes the eye turgid –– and observed that the overgrown vessels significantly regressed as a result. YK-4-279 was found to significantly inhibit ERG/FLI1 right before vessel regression and demonstrated potential as a weapon against these currently permanent diseases. 

Although this project lasted for over two years, Schafer explained that the “most interesting” parts happened in the last 4 to 5 months. At first, their focus was not on treating these diseases per se, but rather on fundamentally understanding the ways in which blood vessels could regress. Nevertheless, they encountered a promising therapeutic avenue along the way.

Unearthing the fundamentals of these complicated retinopathies is critically important. Diseases caused by vessel overgrowth, which primarily affect premature babies and diabetic patients, could result in permanent damage to vision. By identifying a potential treatment route for vessel overgrowth, the OMRF team has started to forge a promising path towards one day curing what is currently incurable.