FDA-Approved Drug May Help Revive Vision in People With Progressive Blinding Disorders

Retinal Ganglion Cells Become Hyperactive in Progressive Blindness

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. Credit: Shubhash Yadav, Richard Kramer lab, UC Berkeley

Test of drug could prove role of hyperactive retinal cells in blindness, potentially leading to better therapies.

Researchers at the University of California, Berkeley, have found that Antabuse (disulfiram) — a drug once widely used to wean alcoholics off of drinking — 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 a chemical — 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.

He realized, however, that the drug disulfiram — also called 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.

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 that link. The researchers are planning to partner with ophthalmologists to conduct a clinical trial of disulfiram on patients with RPThe trial would be carried out on a small set 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 substantially improve low vision and make a real difference in people’s quality of life,” said Kramer, the CH and Annie Li Chair in Molecular Biology of Diseases at UC Berkeley and a member of the campus’s Helen Wills Neuroscience Institute. “Because the drug is already FDA-approved, the regulatory hurdles are low. It wouldn’t be a permanent cure, but right now there are no available treatments 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 today (March 18, 2022) in the journal Science Advances.

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

“If you’re on the drug, and you backslide and take a drink, you will immediately get the worst hangover of your life,” he said, “and that is what makes it a strong deterrent for drinking alcohol.”

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 an RNA interference technique — a type of gene therapy — to knock down the receptor.  Both of these procedures also dramatically improved vision in mice with RP.

Photoreceptor breakdown

Three years ago, Kramer and his colleagues reported that retinoic acid generated sensory noise that interfered with remaining vision in mice with RP in the same way 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 showed that inhibiting the retinoic acid receptor reduced the noise and increased simple light avoidance behaviors in those mice.

But do 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 respond 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 image was shown once again. The investigators found that mice treated with disulfiram or BMS 493 responded quite well, even if the image was blurry. By contrast, mice receiving a placebo failed to respond, even if the image was crisp and clear. 

In a second type of study, the scientists used a special microscope and a fluorescent protein indicator to light up and examine the responses of thousands of cells in the brain to much more complex visual scenes — a Hollywood movie clip, replayed many times. Individual cells in the brains of vision-impaired mice with RP responded preferentially to particular frames in the movie, and their responses were much stronger and more reliable than those of mice that had been treated with disulfiram or BMS 493.

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

Both the behavioral results and the brain imaging results suggest that the drugs improve vision and not just light detection.

“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,” Kramer said.

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 could seek to prevent this by developing chemicals to stop production of retinoic acid by retinaldehyde dehydrogenase, or chemicals that interfere with the retinoic acid receptor.

“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,” Kramer said. “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.”

Reference: “Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration” by Michael Telias, Kevin K. Sit, Daniel Frozenfar, Benjamin Smith, Arjit Misra, Michael J. Goard and Richard H. Kramer, 18 March 2022, Science Advances.
DOI: 10.1126/sciadv.abm4643

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 National Science Foundation (NeuroNex #1707287). Co-authors of the study 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-senior authors.

18 Comments on "FDA-Approved Drug May Help Revive Vision in People With Progressive Blinding Disorders"

  1. Nicole Wheeler | March 19, 2022 at 3:35 am | Reply

    Hello, I recently read the article about a drug used for alcohol treatment could very possibly be used to treat and help people that have macula degenerative disease and I think it’s wonderful,as someone who has recently been diagnosed with with it due to being diabetic to be told that I was going to lose my sight in the near future was devastating and a scary thought for me considering I’m a young 52 years old and have so much to look forward to that now had a future of uncertainty and much sadness to look forward to I felt that my life and future was already over especially when I found out that there was no cure and no solution for my future issue, I’ve been struggling with the constant questions to myself about what kind of life am I to expect with my loss of sight, considering I live alone and have nobody in my life that would be willing to help me and take care of things that I wouldn’t be able to do for myself anymore. I now have some hope after reading about this research and testing that things could very well be better in the future, which is wonderful news for alot of hopeless people. If it was possible I would gladly volunteer for the human trials in order to help in such important efforts, but just giving me back my hopes for a possible future in my life gives me back my smile and my dreams, and I say thank you for that and hopefully things will be better and give back alot of smiles and dreams to alot of hopeless people like me. Good luck with the trials and again thank you!

  2. I have RP and I have MD. I am highly interested in this new treatment. My eyes are blurry and I see snow flakes most of the time. If you are looking for volunteers to test this new drug, I would like to be considered. I am 73 otherwise good health.

  3. I’m interested in restoring my sight my eyes are blurry because I have eye disease .I need help if you can help me but if not thanks any way

  4. Lori Verville | March 20, 2022 at 3:56 am | Reply

    I have family inflicted with RP. My son, 46 yrs old & two brothers have this dreaded eye disease. Are you looking for volunteers?

  5. Please let me know if you are looking for volunteers. My mother has AMD and gets eye injections of Eyelea approximately every 8 weeks in both eyes. We would be interested in volunteering. If you are not looking for volunteers right now, please let me know when you would anticipate doing so. Thank you so much!!

  6. My 80yo mother was diagnosed with RP in her fourties. The disease has reduced her vision to a small, low quality, central field of view. How can I get information regarding participation in the trial? Thanks.

  7. Patricia Clarke | March 20, 2022 at 7:32 am | Reply

    Is there any help available for me.I have been diagnosed with glaucoma.Please let me know.Thank you.🙏

  8. I tried to print this article to give to an older friend that does not have a computer or computer skills and was unable to do so. Why is that?

  9. I had a retina detachment 10 years ago. I can still see a little but very blurry. would i benefit from this new found miracle.

  10. Ernestine Pollard | March 20, 2022 at 3:13 pm | Reply

    I am an 87 year old woman who is losing a lot of my vision in the past months due to AMD and I am very concerned due to the fact that I live alone.

  11. When do you think the drug will be available in the market?

  12. I keep hoping that one day a cure will be found not just for me but for everyone. I have macular degeneration and I know what it is like to have to change your life around. If you need someone to participate in a clinical trial I would be willing to participate.

  13. My husband has RP and would like to be part of a trial. We winter in Lake Havasu City, Arizona and can drive to you. Please let us know.
    Thank you in advance.

  14. How do we get on a list to participate in the trial. My mother has RP and is in good health. Please let us know who to contact for more information. Thank you very much.

  15. Rita Du Plessis | May 31, 2022 at 8:27 pm | Reply

    How do you get on to the list to participate

  16. I am interested if it is going to be trialled

  17. My husband has macular degeneration and would like to be in your clinical trials.

  18. Is there a clinical trialn? I have advanced RP and would like to be cosidered.

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