Drug testing may prove the role of hyperactive retinal cells in blindness and may lead to better treatments-ScienceDaily

This drug has the potential to restore vision in humans with hereditary retinitis pigmentosa (RP), and possibly in other visual impairments, including age-related macular degeneration.

A group of scientists led by Richard Kramer, a professor of molecular and cell biology at the University of California, Berkeley, previously described chemicals as the rods and cones, which are the photoreceptive cells of the retina, gradually die. It has been shown that (retinoic acid) is produced. This chemical causes hyperactivity in the retinal ganglion cells. Retinal ganglion cells normally send visual information to the brain. Hyperactivity interferes with the coding and transfer of information and obscures vision.

However, he found that the drug disulfiram (also known as antabus) inhibits not only the enzymes involved in the body’s ability to break down alcohol, but also the enzymes that produce retinoic acid. In a new experiment, Kramer, who heads the laboratory at the University of California, Santa Barbara (UCSB), and collaborator Michael Goard said that treatment with disulfiram reduces retinoic acid production and is nearly blind in detecting images displayed on computer screens. I found that it makes my mouse much better.

Kramer suspects that retinoic acid may play the same role in people with vision loss. However, experiments to measure ocular retinoic acid have not been performed on humans because they are too invasive.

Disulfiram, which has already been approved for use by the Food and Drug Administration (FDA), may establish that link. Researchers plan to partner with an ophthalmologist to conduct clinical trials of disulfiram in RP patients... The study will be conducted on a small number of people with advanced but not yet complete retinal degeneration.

“By suppressing retinoic acid with drugs like disulfiram, there may be long opportunities to significantly improve vision loss and make a real difference in people’s quality of life,” CH and Annie said.・ Kramer, chairman of Lee’s disease molecular biology, said. A member of the University of California, Berkeley and the Helen Wills Institute of Neuroscience on campus. “Because the drug has already been approved by the FDA, the regulatory hurdles are lower. It’s not a permanent treatment, but there is currently no cure to temporarily improve vision.”

Kramer, Goard, and his colleagues (currently Michael Telias, a former UC Berkeley postdoctoral fellow at the University of Rochester Medical Center, and Kevin Sit at UCSB) will publish their findings in the journal on March 18. Science Advances..

Kramer acknowledged that disulfiram is not suitable for everyone. Combined with alcohol intake, this medicine can cause serious side effects such as headache, nausea, muscle cramps and flushing.

“If you’re taking medicine and you slide back and drink, you’ll quickly get the worst hangover in your life, which is a powerful deterrent to drinking alcohol,” he said.

However, if disulfiram can improve vision, it can look for more targeted treatments that do not interfere with alcohol breakdown or other metabolic functions. Researchers have already tested an drug named BMS 493 that blocks the retinoic acid receptor, and are also using RNA interference technology (a type of gene therapy) to knock down the receptor. Both of these procedures dramatically improved the visual acuity of RP mice.

Breakdown of photoreceptors

Three years ago, Kramer and his colleagues said that tinnitus produced sensory noise that interfered with the rest of the eyesight of RP mice, just as tinnitus interferes with the hearing of vibration-sensitive people. Reported inner ear cells. They showed that inhibition of retinoic acid receptors reduced noise in those mice and increased simple light avoidance behavior.

But do drug-treated mice really look good?

New research provides evidence that they do. First, when the mouse was young and the retina was healthy, it was trained to recognize and respond to a simple image of black and white stripes displayed on a computer screen. One month later, after most rod and pyramidal cells had degenerated, the image was displayed again. Researchers have found that mice treated with disulfiram or BMS493 respond very well, even with blurred images. In contrast, placebo-treated mice did not respond, even though the images were crisp and crisp.

In the second type of study, scientists used special microscopes and fluorescent protein indicators to illuminate and examine the response of thousands of cells in the brain to much more complex visual scenes (Hollywood movie clips). rice field. Individual cells in the brain of RP vision-impaired mice responded preferentially to specific frames of the movie, and their response was much stronger and more reliable than mice treated with disulfiram or BMS493. ..

The response was so reliable that researchers could infer which particular scene caused the cellular response, but only in mice treated with one of the drugs.

Both behavioral and brain imaging results suggest that the drug improves visual acuity as well as light detection.

“The treated mice actually look better than the non-drug mice. These particular mice could barely detect images in the late stages of this degeneration. I think it’s very dramatic. “I will,” said Kramer.

In 2019, Kramer and his team unraveled the mechanism behind the hyperactivity caused by degeneration. They found that retinoic acid, a well-known signal of embryonic growth and development, floods the retina when photoreceptors (dim light-sensitive rod cells and pyramidal cells required for color vision) die. discovered. This is because the photoreceptors are clogged with a photosensitive protein containing a retinaldehyde called rhodopsin. When retinal aldehyde is no longer absorbed by rod and pyramidal cells, it is converted to retinoic acid by an enzyme called retinal dehydrogenase.

Next, retinoic acid stimulates retinal ganglion cells by attaching to retinoic acid receptors. It is these receptors that make the ganglion cells hyperactive, creating a constant topic of activity that sinks the visual scene and prevents the brain from picking up signals from noise. Drug developers can try to prevent this by developing chemicals that stop the production of retinoic acid by retinal dehydrogenase, or block retinoic acid receptors.

“If disulfiram is given to people with impaired vision and their vision improves even a little, the results are great in their own right, but the retinoic acid pathway is also strongly involved in vision loss,” Kramer said. Mr. says. “And it will be an important proof of concept that has the potential to drive a whole new strategy to help develop new drugs and improve vision.”

This work is supported by grants from the National Institutes of Health (R01EY024334, P30EY003176) and the Blind Fighting Foundation to Kramer, and by the National Institutes of Health (R01NS121919) and the National Science Foundation (NeuroNex # 1707287) to Gordo. I did. The co-authors of this study are Terias, Daniel Frozenfer, Benjamin Smith, Argit Misra, and Sit at the University of California, Berkeley. Telias and Sit are co-lead authors. Goard and Kramer are co-authors.