A new study from the Medical College of Georgia has recently identified why many patients do not benefit from the most utilized therapy for neovascular age-related macular degeneration (AMD) – a leading cause of blindness.
A gene previously implicated in the development of causing clogged arteries in the heart, otherwise known as atherosclerotic lesions in coronary arteries, could be key to understanding why many continue to suffer from AMD, despite receiving the most popular treatments.
A condition characterized by abnormal blood vessel growth in the back of the eye, AMD is known to be one of the leading causes of blindness that is highly prevalent in older adults and those with diabetes, obesity and many other chronic metabolic diseases.
According to an AU press release, anti-VEGF therapy, which blocks the vascular endothelial growth factor and keeps excessive blood vessel growth at bay, is usually the first line of defense.
However, Dr. Yuqing Huo, the director of the Vascular Inflammation Program at MCG’s Vascular Biology Center, said the anti-VEGF therapy only works well for about a third of the patients suffering from a particular form of AMD.
“The reason is that the excess vasculature is often accompanied by the growth of fibroblast cells,” he said.
Collagen and several other proteins produced by these fibroblast cells accumulate outside of the vascular cells and eventually lead to scarring in the eye, also known as fibrosis.
Fibrosis then keeps the excess vasculature from being suppressed by anti-VEGF treatments.
“We show, for the first time in this study, that many fibroblast cells are actually produced by these excessive endothelial cells. We must find a way to prevent this from happening,” Huo said.
Huo and his team believe the answer may lie in targeting the adenosine receptor 2A (Adora2a) – a G-protein-coupled adenosine receptor found in high levels in the brain, immune cells and blood vessels.
“Adora2a has been reported to be crucial in modulating inflammation, myocardial oxygen consumption and coronary blood flow,” stated a press release from MCG. “Adenosine, a metabolite produced by cells under conditions of stress, injuries, and lack of oxygen, can activate Adora2a to protect our body from injury.”
In excess, adenosine can also lead to excessive blood vessel growth.
Through their current research, Huo and his colleagues found a high-level or persistent adenosine-activated Adora2a signal could transform endothelial cells, otherwise known as the luminal cells of the vasculature, into activated fibroblast cells and eventually cause fibrosis.
By blocking this Adora2a signal, Huo and his colleagues hypothesize they can prevent fibrosis from developing.
“We have previously demonstrated that blocking Adora2a can reduce excessive blood vessel growth, which happens in the early stages of AMD,” said Dr. Yongfeng Cai, a postdoctoral fellow in Huo’s lab and a member of the research team.
Using genetically engineered mice that develop fibrosis in the backs of their eyes, researchers delivered an Adora2a agonist (KW6002), which binds to the receptor and blocks its function.
“We also studied mice that had Adora2a removed from only the vascular endothelial cells,” said Dr. Qiuhua Yang, a postdoctoral fellow with Huo and the first author on this study. “All of these mice demonstrated decreased fibrosis in the eye.”
Now Huo’s team has an eye toward generating an antibody that could recognize Adora2a.
With research supported by a National Institutes of Health K99 – awarded to Yang – and funds from the National Eye Institute, Huo said the antibody could easily be delivered via an injection to the back of the eyes, an approach often used in eye clinics, to block the activation of adenosine to Adora2a.
“An antibody could really block both excessive blood vessel growth, the early stage of AMD, and fibrosis, the late stage of AMD,” Huo said. “Our findings indicate that blocking Adora2a can certainly target multiple stages of this disease, which might be much more efficient than current treatments.”
These novel findings were published and recently selected as the cover image for “Science Translational Medicine.”
To read the full study, visit: https://www.science.org/doi/10.1126/scitranslmed.adk3868
