Antabuse may help revive vision in progressive blinding disorder

Antabuse (Disulfiram) is an inhibitor of aldehyde dehydrogenase, which is directly relevant to its role in curbing alcohol consumption. It is previously used in treating patients addicted to alcohol and/or cocaine consumption. Antabuse undermines dopamine transmission and dampen the euphoric and stimulant effect of cocaine.

 

Researchers at the University of California, Berkeley, have however discovered that Antabuse helps to improve sight in mice with retinal degeneration.

The drug may revive sight in humans with the inherited disease retinitis pigmentosa (RP), and perhaps in other vision disorders, including age-related macular degeneration.

A group of scientists led by Richard Kramer, UC Berkeley professor of molecular and cell biology, had previously shown that retinoic acid is produced when light-sensing cells in the retina, called rods and cones, gradually die off. This chemical causes hyperactivity in retinal ganglion cells, which ordinarily send visual information to the brain. The hyperactivity interferes with their encoding and transfer of information, obscuring vision.

However, he realised that Antabuse inhibits not only enzymes involved in the body’s ability to degrade alcohol, but also enzymes that make retinoic acid. In new experiments, Kramer and collaborator Michael Goard, who directs a lab at UC Santa Barbara (UCSB), discovered that treatment with disulfiram decreased the production of retinoic acid and made nearly-blind mice much better at detecting images displayed on a computer screen.

In 2019, Kramer and his team laid out the mechanism behind hyperactivity caused by degeneration. They found 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, needed for color vision — die. That’s because photoreceptors are packed with light-sensitive proteins called rhodopsin, which contain retinaldehyde. When the retinaldehyde can no longer be absorbed by rods and cones, it is converted to retinoic acid by an enzyme called retinaldehyde dehydrogenase.

The retinoic acid, in turn, stimulates the retinal ganglion cells by adhering to retinoic acid receptors. It’s these receptors that make 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 developers may seek to prevent this by developing chemicals that would stop the production of retinoic acid by retinaldehyde dehydrogenase, or chemicals that interfere with the retinoic acid receptor.

The researchers are planning to partner with ophthalmologists to conduct a clinical trial of disulfiram on patients with RP. The trial would be carried out on a small set of people with advanced, but not yet complete, retinal degeneration.