Many times, the purpose of vision research is to identify genes that cause diseases, such as age-related macular degeneration and Leber Congenital Amaurosis, and then either stop the gene from causing damage or fix the troublesome gene entirely. Two research projects are focused on just that and the results are promising.
Scientists from the lab of Yuqing Huo, MD, the director of the Vascular Inflammation Program at Medical College of Georgia at Augusta University, have found that a gene that is associated with the development of lesions in coronary arteries could be the reason why many people with age-related macular degeneration don’t benefit from anti-VEGF therapy. Anti-VEGF therapy is the first line of defense when someone has age-related macular degeneration, since it blocks excessive blood vessel growth in the eye.
Huo and his colleagues found that the blood vessel growth is accompanied by the growth of fibroblast cells. These cells produce collagen and other proteins that collect outside of the vascular cells, leading to scarring of the eye. This scarring prevents the extra blood vessels from being suppressed by the anti-VEGF therapy. Since this study showed that these fibroblast cells are produced by excessive endothelial cells, there must to be a way to prevent this from happening.
Researchers believe that the way to prevent the fibroblast cells from forming is by targeting the adenosine receptor 2A (Adora2a). This G-protein-coupled adenosine receptor is found in high levels in the brain, immune cells, and blood vessels. Adora2a is known to a crucial role in regulating inflammation, heart tissue oxygen consumption, and coronary blood flow. Adenosine is a metabolite produced by the cells under conditions of stress or injury, and it can activate Adora2a to protect our body from injury.
The trouble comes when there is too much adenosine, leading to excessive blood vessel growth. Huo’s lab found that high levels of adenosine-activated Adora2a signaling can transform the endothelial cells of the blood vessels into fibroblast cells and this leads to scarring. Huo and his colleagues feel that blocking this receptor can prevent this from happening. They studied genetically engineered mice that had scarring in the back of their eyes. Researchers delivered KW6002 to the mice’s eyes. KW6002, as Adora2a agonist, (a substance that mimics the action of a neurotransmitter when it binds to a specific receptor), successfully bound to the Adora2a receptor and blocked its function, which led to decreased scarring. As a result of this discovery, researchers are working on developing an antibody that would recognize Adora2A and block both the excessive blood vessel growth and scarring.
What about fixing the genes responsible for a type of inherited blindness? Is it possible to repair a gene in the human body? A clinical trial led by principal investigator Eric Pierce, MD, PhD, at Massachusetts Eye and Ear shows that the answer is yes.
A clinical trial of CRISPR-Cas9 gene editing was done on 14 individuals, 12 adults (ages 17 to 63) and two children (ages 10 and 14) who were born with a form of Leber congenital amaurosis. This is an inherited form of blindness caused by mutations in the centrosomal protein 290 (CEP290) gene. The CRISPR-Cas9 is a gene editing toolkit that works like a GPS-guided scissor to cut out a part of the mutated genome, leaving behind a functional gene. The goal of this trial was to inject CRISPR to reach the retina and restore the ability to produce the gene and protein responsible for light-sensing cells. Participants in this trial received a single injection of a CRISPR/Cas9 genome editing medicine, EDIT-101 in one eye. This trial was focused first on safety and second on efficacy.
Thankfully, there were no issues with safety. For efficacy, researchers measured four outcomes: best-corrected visual acuity (BCVA); dark-adapted full-field stimulus testing (FST), visual function navigation (VNC) and vision-related quality of life. Of the 14 participants, 11 has at least one improvement in one of these outcomes, six participants had improved in two or more outcomes. Four participants had meaningful improvements in BCVA. Six participants showed improvements in cone-mediated vision as shown by FST. One trial participant mentioned that after the procedure, the participant was able to see the small lights on a coffee machine—something that person couldn’t do before.
Two adults in the trial received a low-dose therapy, five adults received mid-dose and the remaining five received a high-dose treatment. The two children in the study received a mid-dose. This trial was the first to include children with LCA receiving gene therapy and the treatment improved their daytime vision. Researchers hope future studies will examine ideal dosing levels and determine whether the treatment is more effective for certain age groups.
For a long time, it was believed that nothing could be done about defective genes. Thanks to research projects like those at Medical College of Georgia and Massachusetts Eye and Ear, we are now approaching a future where genes can be modified and even repaired.
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