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Researchers at the University of California, Berkeley have found that a drug once widely used to wean alcoholics off alcohol helps improve eyesight in mice with retinal degeneration.

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

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

He realized, however, that the drug disulfiram – also called Antabuse – inhibits not only the enzymes involved in the body’s ability to break down alcohol, but also the enzymes that make retinoic acid. In new experiments, Kramer and collaborator Michael Goard, who runs a lab at UC Santa Barbara (UCSB), found that disulfiram treatment decreased retinoic acid production and made near-blind mice much better at detecting images displayed on a computer screen.

Kramer suspects that retinoic acid plays an identical role in people with vision loss. But experiments measuring retinoic acid in the eye have not been done on humans because they would be too invasive.

Disulfiram – which is already approved for use by the Food and Drug Administration (FDA) – could establish this link. Researchers plan to partner with ophthalmologists to conduct a clinical trial of disulfiram in patients with RP. The trial would be carried out on a small group of people with advanced, but not yet complete, retinal degeneration.

“There may be a long window of opportunity in which suppressing retinoic acid with drugs like disulfiram could dramatically improve low vision and make a real difference in people’s quality of life,” Kramer said. holder of the CH and Annie Li Chair in Molecular Biology of Diseases at UC Berkeley and a member of the Helen Wills Neuroscience Institute on campus. “Because the drug is already FDA-approved, the regulatory hurdles are low. It wouldn’t be a permanent cure, but currently there are no treatments available that even temporarily improve vision.”

Kramer, Goard and their colleagues — Michael Telias, a former UC Berkeley postdoctoral fellow now at the University of Rochester Medical Center, and Kevin Sit of UCSB — will publish their findings March 18 in the journal Scientists progress.

Kramer acknowledged that disulfiram may not be for everyone. When combined with alcohol consumption, the drug can cause serious side effects, including headache, nausea, muscle cramps, and flushing.

“If you’re on drugs and backsliding and having a drink, you’ll immediately have the worst hangover of your life,” he said, “and that’s what makes it a powerful way to deterrent to alcohol consumption”.

But if disulfiram can improve vision, more targeted therapies could be sought that do not interfere with alcohol breakdown or other metabolic functions. The researchers previously tested an experimental drug called BMS 493 that inhibits the retinoic acid receptor, and they also used an RNA interference technique – a type of gene therapy – to knock down the receptor. Both of these procedures also significantly improved vision in mice with RP.

Photoreceptor degradation

Three years ago, Kramer and colleagues reported that retinoic acid generated sensory noise that interfered with remaining vision in mice with RP similar to ringing in the ears, known as tinnitus, can interfere with hearing in people who lose sensitivity to vibrations. inner ear cells. They showed that inhibition of the retinoic acid receptor reduced noise and increased simple light avoidance behaviors in these mice.

But do the mice treated with the drugs actually see better?

The new study provides evidence that they do. First, when the mice were young and had healthy retinas, they were trained to recognize and react to a simple image of black and white stripes displayed on a computer screen. A month later, after most of the rods and cones had degenerated, the picture was shown again. The researchers found that mice treated with disulfiram or BMS 493 responded quite well, even though the image was blurry. In contrast, mice given a placebo did not respond, although the image was sharp and clear.

In a second type of study, scientists used a special microscope and a fluorescent protein indicator to illuminate and examine the responses of thousands of cells in the brain to much more complex visual scenes – a Hollywood movie clip, replayed several time. Individual brain cells from visually impaired mice with RP responded preferentially to particular film frames, and their responses were much stronger and more reliable than those from mice that had been treated with disulfiram or BMS 493.

The responses were so reliable, Kramer said, that investigators were able to deduce which specific scene triggered the cell’s response, but only in mice that had been treated with one of the drugs.

Behavioral findings and brain imaging findings suggest that the drugs improve vision, not just light detection.

“The treated mice really see better than the unmedicated mice. These particular mice could barely detect images at this late stage of degeneration. I think that’s pretty dramatic,” Kramer said.

In 2019, Kramer and his team explained the mechanism of 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 – rods, sensitive to low light, and cones, necessary for color vision – die. This is because photoreceptors are filled with light-sensitive proteins called rhodopsin, which contain retinaldehyde. When retinaldehyde can no longer be absorbed by rods and cones, it is converted to retinoic acid by an enzyme called retinaldehyde dehydrogenase.

Retinoic acid, in turn, stimulates retinal ganglion cells by adhering to retinoic acid receptors. It is these receptors that make the ganglion cells overactive, creating a constant buzz of activity that overwhelms the visual scene and prevents the brain from picking up the signal from the noise. Drug developers might seek to prevent this by developing chemicals to stop the production of retinoic acid by retinaldehyde dehydrogenase, or chemicals that interfere with the retinoic acid receptor.

“If a visually impaired human were given disulfiram and their vision improved even a little, that would be a great outcome in itself. But it would also strongly implicate the retinoic acid pathway in vision loss,” Kramer said. . “And that would be an important proof of concept that could lead to the development of new drugs and a whole new strategy to help improve vision.”

The work was supported by grants awarded to Kramer from the National Institutes of Health (R01EY024334, P30EY003176) and the Foundation for Fighting Blindness and to Goard from the National Institutes of Health (R01NS121919) and the National Science Foundation (NeuroNex #1707287) . The study’s co-authors are Telias, Daniel Frozenfar, Benjamin Smith, and Arjit Misra of UC Berkeley and Sit of UC Santa Barbara. Telias and Sit are co-first authors; Goard and Kramer are co-lead authors.