• Antabuse may help revive vision in peopl

    From ScienceDaily@1:317/3 to All on Friday, March 18, 2022 22:30:36
    Antabuse may help revive vision in people with progressive blinding
    disorders
    Test of drug could prove role of hyperactive retinal cells in blindness, potentially leading to better therapies

    Date:
    March 18, 2022
    Source:
    University of California - Berkeley
    Summary:
    Animal and cell studies show that as retinal cells die in
    degenerative eye diseases, they make other cells hyperactive,
    creating noise that further obscures vision. Tests to prove this
    in humans are hard to conduct, however. Antabuse, an approved drug
    used to wean people off alcohol, should tamp down this hyperactivity
    and conclusively show whether hyperactivity plays a role in humans,
    potentially driving work to find better drugs to help those with
    progressive vision loss.



    FULL STORY ========================================================================== Researchers at the University of California, Berkeley, have found that
    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 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, 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 March 18 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." 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.


    ========================================================================== Story Source: Materials provided by
    University_of_California_-_Berkeley. Original written by Robert
    Sanders. Note: Content may be edited for style and length.


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

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220318161440.htm

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