A pharmacological trial might demonstrate the function of overactive retinal cells in blindness, perhaps leading to improved therapeutics.
According to animal and cell research, when retinal cells die in degenerative eye illnesses, they cause other cells to become hyperactive, causing noise that further obscures vision. Human tests to show this are, however, difficult to carry out. Antabuse, a licensed treatment used to wean individuals off alcohol, should dampen this hyperactivity and definitively establish if hyperactivity has a role in humans, thereby fueling research into new drugs to aid persons with progressive visual loss.
Researchers at the University of California, Berkeley, discovered that a medicine formerly extensively used to assist alcoholics quit drinking improves vision in mice with retinal degeneration.
The medicine has the potential to restore sight in people with the genetic condition retinitis pigmentosa (RP), as well as other visual problems such as age-related macular degeneration.
Previously, a group of scientists headed by Richard Kramer, UC Berkeley professor of molecular and cell biology, demonstrated that retinoic acid is created when light-sensing cells in the retina known as rods and cones die off gradually. This substance stimulates retinal ganglion cells, which normally convey visual information to the brain. The hyperactivity interferes with their information encoding and transmission, blurring eyesight.
However, he discovered that the medication disulfiram, better known as Antabuse, inhibits not just enzymes involved in the body’s capacity to digest alcohol, but also enzymes involved in the production of retinoic acid. Kramer and coauthor Michael Goard, who leads a lab at UC Santa Barbara (UCSB), showed that disulfiram therapy reduced retinoic acid synthesis and improved the detection of pictures presented on a computer screen in nearly-blind mice.
Kramer believes that retinoic acid serves a similar impact in patients who have visual loss. However, since detecting retinoic acid in the eye would be excessively intrusive, no human studies have been conducted.
Disulfiram, which is already licensed by the Food and Drug Administration (FDA), may be able to demonstrate that relationship.
The researchers want to collaborate with ophthalmologists to undertake a clinical study of disulfiram on RP patients. The experiment would include a small group of persons who have advanced but not yet total retinal degeneration.
“There may be a long window of opportunity where suppressing retinoic acid with drugs like disulfiram could significantly 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 Helen Wills Neuroscience Institute on campus. “The regulatory obstacles are modest since the medicine has already been authorized by the FDA. It wouldn’t be a permanent cure, but there are currently no medicines available that even temporarily enhance eyesight.”
Kramer, Goard, and their colleagues, including Michael Telias, a former UC Berkeley postdoctoral researcher currently at the University of Rochester Medical Center, and Kevin Sit of UCSB, will publish their results in the journal Science Advances on March 18.
Kramer admitted that disulfiram may not be suitable for everyone. When coupled with alcohol, the medicine may cause serious adverse effects such as headache, nausea, muscular cramps, and flushing.
“If you’re on the medicine and you take a drink, you’ll suffer the worst hangover of your life,” he said, “and that’s why it’s such a powerful barrier to consuming alcohol.”
However, if disulfiram does enhance eyesight, more focused medicines that do not interfere with alcohol breakdown or other metabolic activities might be pursued. The researchers have previously tried an experimental medicine called BMS 493, which inhibits the retinoic acid receptor, as well as an RNA interference approach (a sort of gene therapy) to knock down the receptor. Both of these techniques significantly improved eyesight in RP mice.
Kramer and colleagues reported three years ago that retinoic acid produced sensory noise that interfered with residual vision in mice with RP, in the same way that ringing in the ears, known as tinnitus, may interfere with hearing in humans who are losing vibration-sensitive cells in the inner ear. Inhibiting the retinoic acid receptor decreased noise and boosted simple light avoidance responses in those mice.
But, do the medications genuinely improve the vision of mice?
The latest research demonstrates that they do. First, the mice were taught to identify and react to a basic visual of black and white stripes flashed on a computer screen while they were young and had healthy retinas. The picture was exhibited again a month later, when most of the rods and cones had decayed. The researchers discovered that mice given disulfiram or BMS 493 reacted effectively even when the picture was unclear. Mice given a placebo, on the other hand, did not react even when the visual was sharp and clear.
In a second study, the researchers used a special microscope and a fluorescent protein indicator to light up and assess the reactions of hundreds of cells in the brain to far more complex visual stimuli — a Hollywood movie clip that was repeated multiple times. Individual cells in the brains of vision-impaired mice with RP reacted preferentially to certain frames in the movie, and their responses were more stronger and more consistent than those of animals treated with disulfiram or BMS 493.
The reactions were so consistent, according to Kramer, that the researchers were able to determine which precise picture had prompted the cell’s response, but only in mice given with one of the medications.
Both the behavioral and brain imaging data indicate that the medicines increase vision rather than merely light detection.
“Treated mice see clearly better than untreated mice. At this late stage of degeneration, these mice could scarcely recognize pictures at all. That strikes me as extremely dramatic “Kramer said.
Kramer and his colleagues described the mechanism behind hyperactivity induced by degeneration in 2019. They discovered that retinoic acid, which is well-known as a signal for embryonic growth and development, floods the retina when photoreceptors (the rods, which are sensitive to low light, and the cones, which are required for color vision) die. This is due to the fact that photoreceptors are densely packed with light-sensitive proteins called rhodopsin, which contain retinaldehyde. When retinaldehyde can no longer be absorbed by rods and cones, an enzyme called retinaldehyde dehydrogenase converts it to retinoic acid.
By attaching to retinoic acid receptors, retinoic acid activates retinal ganglion cells. These receptors cause ganglion cells to become hyperactive, resulting in a continual buzz of activity that drowns out the visual world and inhibits the brain from distinguishing between signal and noise. Drug makers might try to avoid this by creating drugs that inhibit retinoic acid synthesis by retinaldehyde dehydrogenase or compounds that interfere with the retinoic acid receptor.
“If a blind person was given disulfiram and their eyesight improved even little, that would be a fantastic result in and of itself. However, it would strongly suggest that the retinoic acid pathway is involved in vision loss “Kramer said. “And that would be a significant proof of concept that might drive new medication development and a whole different method for assisting in the improvement of eyesight.”
Kramer received funding from the National Institutes of Health (R01EY024334, P30EY003176) and the Foundation for Fighting Blindness, while Goard received grants from the National Institutes of Health (R01NS121919) and the National Science Foundation (NeuroNex #1707287). Telias, Daniel Frozenfar, Benjamin Smith, and Arjit Misra of UC Berkeley, as well as Sit of UC Santa Barbara, are co-authors of the paper. Telias and Sit are joint first authors, while Goard and Kramer are joint senior authors.