Researchers at the University of California, Berkeley, have discovered that a drug used to wean alcoholics off of drinking aids in improving sight in mice with retinal degeneration.
People with the inherited illness retinitis pigmentosa (RP) may revive sight, particularly in other vision disorders, such as age-related macular degeneration.
A group of scientists led by Ridd Kramer, a UC Berkeley professor of molecular and cell biology, had previously shown that a chemical retinoic acid was activated when light-sensing cells in the retina, called rods and cones, died off. This chemical causes hyperactivity in retinal ganglion cells, which often send visual information to the brain. This hyperactivity affects their encode and transfer of information, obscuring vision.
Despite his findings, disulfiram, which is also known as Antabuse, inhibits non-invasive enzymes involved in the body''s ability to degrade alcohol, but also enzymes that make retinoic acid. In new experiments, Kramer and his collaborator Michael Goard, who operates a laboratory at UC Santa Barbara, discovered that disulfiram reduced the production of retinoic acid, making nearly-blind mice much better at detecting images on a computer screen.
Kramer believes that retinoic acid has an identical role in people with vision impairment. However, experiments using retinoic acid in the eyes have not been conducted on humans, because they would be too invasive.
Disulfiram, which has been approved for use by the Food and Drug Administration (FDA) might establish that link. Researchers are planning to working with ophthalmologists to conduct a clinical trial of disulfiram on patients with RP. The trial would be carried out on a small group of individuals with advanced, but not yet complete retinal degeneration.
Treatments such as disulfiram may even help with low vision, according to Kramer, the CH and Annie Li Chair in Molecular Biology of Diseases at UC Berkeley. Unfortunately, the regulatory barriers are low. It wouldn''t be a permanent cure, but there are still certain therapies that even temporarily improve vision.
Michael Telias, a former UC Berkeley postdoctoral researcher now at the University of Rochester Medical Center, and Kevin Sit of the UCSB will publish their findings on March 18 in the journalScience Advances.
Disulfiram may not be for everyone, according to Kramer. It may have severe side effects, including headaches, nausea, muscle cramps, and flushing.
If youre on the drug, and you backslide and take a cocktail, you will immediately get the worst hangover of your life, according to the president, and that is why it is a powerful deterrent for drinking alcohol.
If disulfiram is able to improve vision, then there are other approaches to combat alcohol breakdown or other metabolic functions. BMS 493, a technique developed by the RNA, and has also enhanced vision in mice with RP.
Three years ago, Kramer and his colleagues said that retinoic acid induced sensory disturbance that interfered with remaining vision in mice with RP in the same manner that ringing in the ears, known as tinnitus, can interfere with hearing in people who are losing vibration-sensitive cells in the inner ear. They demonstrated that inhibiting the retinoic acid receptor reduced the noise and increased simple light avoidance behaviors in those mice.
Are mice treated with these medications actually showing signs of improvement?
Firstly, when the mice were young and had healthy retinas, they were trained to recognize and respond to a simple image of black and white stripes shown on a computer screen. A month later, when the rods and cones were removed, the image was once again shown. Despite the fact that the mice receiving a placebo failed to respond, even if the image was crisp and clear.
The researchers used a special microscope and a fluorescent protein indicator to investigate and illuminate the responses of tens of thousands of cells in the brain to much more complex visual scenes from a Hollywood film clip, often replayed. Individual cells in the brains of vision-impaired mice with RP responded preferentially to specific scenes in the film, and their responses were much stronger and more reliable than those of mice who had been treated with disulfiram or BMS 493.
Kramer said the responses were so reliable that the investigators could deduce which particular scene had triggered the cells response, although they only found mice who had been treated with one of the drugs.
Both behavioral and brain imaging findings suggest that drugs improve vision rather than light detection.
Treated mice are actually capable of seeing better than those without taking medication. At this early stage of degeneration, these particular mice could barely detect images. I think that''s quite dramatic.
In 2019, Kramer and his team explored the root of hyperactivity induced by degeneration. They discovered that retinoic acid, which is well-known as a signal for growth and development in embryos, floods the retina when photoreceptors the rods, sensitive to dim light, and the cones, died. That is because photoreceptors are packed with light-sensitive proteins called rhodopsin, which convert the retinaldehyde to retinoic acid. This enzyme
The retinoic acid is boosted retinal ganglion cells by adhering to retinoic acid receptors. Its receptors that make the ganglion cells hyperactive, creating a constant buzz of activity that submerges the visual scene and prevents the brain from picking out the signal from noise. Drug manufacturers may try to prevent this by developing chemicals to stop the production of retinoic acid by retinaldehyde dehydrogenase or chemicals that interfere with the retinoic acid
If a vision impairment human had been given disulfiram and their vision improved, it would be a great outcome in itself. However, it might heavily implicate the retinoic acid pathway in vision loss, according to Kramer. That would be an important proof of concept that might enable new medication development and a whole new approach for improving vision.