Studies by researchers at the University of California (UC), Berkeley, suggest that a drug once widely used to help alcoholics abstain from drinking can also work to improve sight in mice with retinal degeneration, by inhibiting synthesis of retinoic acid (RA).
Findings from the research, which has been led Richard Kramer, PhD, UC Berkeley professor of molecular and cell biology, indicate that the drug, disulfiram—commonly known as antabuse—might also help to revive sight in humans with retinitis pigmentosa (RP), or other vision disorders, including age-related macular degeneration (AMD).
“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,” Kramer said. “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.”
Reporting on their findings in Science Advances (“Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration”), Kramer and colleagues concluded, “… by inhibiting RA, we reveal a new therapeutic strategy for mitigating vision loss that may be applicable across a wide range of photoreceptor degenerative disorders, regardless of the underlying etiology.”
Age-related macular degeneration and retinitis pigmentosa are the most prevalent photoreceptor degenerative disorders, resulting in impaired vision, and potentially blindness in hundreds of millions of people worldwide, the authors explained. “Both AMD and RP progress gradually, with retinal light responses and visual perception declining over years to decades.”
Scientists led by Kramer had previously shown that RA is produced when the light-sensing rods and cones in the retina gradually die off. The retinoic acid causes hyperactivity in the retinal ganglion cells (RGCs) that normally send visual information to the brain. This hyperactivity interferes with the encoding and transfer of information. The authors further noted, that while RA is the molecular trigger of RGC hyperactivity, “ … whether this interferes with visual perception is unknown.”
Kramer realized that disulfiram inhibits not only enzymes involved in the body’s ability to degrade alcohol, but also enzymes that make RA. Through their newly reported research, Kramer and collaborator Michael Goard, PhD, who directs a lab at UC Santa Barbara (UCSB), discovered that treatment with disulfiram decreased the production of retinoic acid. Nearly-blind mice that were treated using the drug were then much better at detecting images displayed on a computer screen.
In their newly reported paper the researchers also tested the experimental drug BMS 493, which inhibits the retinoic acid receptor (RAR), and they have also investigated the effects of using RNA interference to knock down the receptor. Both of these procedures dramatically improved vision in mice with RP.
Three years ago, Kramer and colleagues reported that RA 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 RAR reduced the noise and increased simple light avoidance behaviors in those mice.
Importantly, the new study provides evidence that mice treated with the drugs really do see better. First, when the animals 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 microscopy technique 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 not been treated with disulfiram or BMS 493. “Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice,” the team noted. “In vivo Ca2+ imaging shows that disulfiram sharpens orientation tuning of visual cortical neurons and strengthens fidelity of responses to natural scenes.”
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. “… inhibiting RA-induced changes can mitigate impairment of simple or complex visual functions, even in mice with late-stage photoreceptor degeneration,” the team commented. “These findings suggest RA synthesis or signaling inhibitors as tools for therapeutic improvement of low vision in humans … Our results show that inhibiting RAR also improves vision.” The investigators acknowledged that it remains to be seen whether disulfiram will improve vision in humans, “ … but the barriers to answering this question seem relatively low,” they pointed out.
“Treated mice really see better than mice without the drugs,” Kramer stated. “These particular mice could barely detect images at all at this late stage of degeneration. I think that that’s quite dramatic.”
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 RA by an enzyme called retinaldehyde dehydrogenase.
The RA, in turn, stimulates the retinal ganglion cells by adhering to RARs. 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. “… our studies have shown that RA-induced hyperactivity is maladaptive, adding background noise that obscures signals that are already attenuated by the loss of photoreceptors,” they wrote. Drug developers could seek to prevent this by developing chemicals to stop production of RA by retinaldehyde dehydrogenase, or chemicals that interfere with the retinoic acid receptor.
Vision restoration therapies are aimed, at least for now, at the small fraction of patients with end-stage photoreceptor degeneration, but treatments targeting the RA pathway may be relevant to the much larger patient population with low vision,” the authors suggested. “Moreover, reducing RGC hyperactivity with RA inhibitors might be beneficial even after all the photoreceptors have degenerated and light perception is absent.”
The scientists 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. “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, who is also 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 acknowledged that disulfiram may not be a great option 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.” Nevertheless, the team suggested, “If disulfiram shows efficacy, then it could be administered orally, but local ocular delivery involving a new drug formulation might ultimately be more appropriate for avoiding the undesired systemic consequences associated with alcohol consumption.”
