A key to restoring sight may be held in a drug that treats alcoholism

Mar. 18, 2022

Researchers may have found a way to revive some vision loss caused by age-related macular degeneration – the leading cause of blindness – and the inherited disease retinitis pigmentosa (RP), a rare genetic disorder that causes the breakdown and loss of cells in the retina. The drug disulfiram – marketed under the brand name Antabuse – used to treat alcoholism, may hold the key to restoring this vision loss.

Michael Telias, Ph.D.

“We knew the pathway that the drug disulfiram blocks to treat alcoholism was very similar to the pathway that’s hyper-activated in degenerative blindness,” said Michael Telias, Ph.D., assistant professor of Ophthalmology, Neuroscience, and Center for Visual Science at the University of Rochester Medical Center, and first author on the paper out today in Science Advances. “We expected some improvement, but our findings surpassed our expectations. We saw vision that had been lost over a long period of time preserved in those who received the treatment.”

In research involving mice, researchers found disulfiram helped restore some vision by suppressing the sensory noise in the inner retina caused by dying photoreceptors in the outer retina that is brought on by the progression of outer retinal degeneration (such as age-related macular degeneration or retinitis pigmentosa), in which the light-sensing cells called “photoreceptors” slowly die over years.. In past research, as a postdoctoral fellow at UC Berkeley, Telias found that as photoreceptors die off it disrupts the function of the inner retina. This causes the sensory noise that ultimately becomes a barrier between the surviving photoreceptors and the brain. This latest research, led by Richard Kramer, Ph.D., professor at the University of California, Berkeley, and Michael Goard, Ph.D., Assistant Professor at University of California, Santa Barbara, found that disulfiram can target that sensory noise, allowing the surviving photoreceptors in the outer retina to complete the signal to the brain and ultimately restore some vision. They found that nearly blind mice, treated with disulfiram, were much better at detecting images on a computer screen.

Mouse retinal ganglion cells_Telias_Paper_March2022
A mouse retinal ganglion cell (green), which becomes hyperactive in degenerative vision disorders. Other retinal cell types are labeled in blue. Hyperactivity interferes with the proper transfer of signals from the retina to the brain. Richard Kramer's lab at UC Berkeley has discovered what causes hyperactivity and has identified drugs that interfere with the process, and by doing so, improve vision. (Image credit: Shubhash Yadav, Kramer lab)

“Treated mice really see better than mice without the drugs. These particular mice could barely detect images at all at this late stage of degeneration. I think that that's quite dramatic," said Kramer. "If a vision impaired human were given disulfiram and their vision got better, even a little bit, that would be a great outcome in itself. But it would also strongly implicate the retinoic acid pathway in vision loss. And that would be an important proof of concept that could drive new drug development and a whole new strategy for helping to improve vision."

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. Disulfiram does have some severe side-effects if alcohol is consumed while taking it – including headache, nausea, muscle cramps and flushing. But if disulfiram can improve vision, more targeted therapies could be sought that don't interfere with alcohol breakdown or other metabolic functions. The researchers have already tested an experimental drug named BMS 493 that inhibits the receptor for retinoic acid, and they have also used gene therapy to knock down the receptor.  Both of these procedures also dramatically improved vision in mice with RP.

Other authors include co-first author Kevin Sit, Ph.D., of University of California, Santa Barbara, Daniel Frozenfar, Benjamin Smith and Arjit Misra of University of California, Berkeley. The work was funded by National Institutes of Health and National Science Foundation.