• Correcting night blindness in dogs

    From ScienceDaily@1:317/3 to All on Tuesday, March 22, 2022 22:30:46
    Correcting night blindness in dogs

    Date:
    March 22, 2022
    Source:
    University of Pennsylvania
    Summary:
    Researchers have developed a gene therapy that restores dim-light
    vision in dogs with a congenital form of night blindness, offering
    hope for treating a similar condition in people.



    FULL STORY ========================================================================== People with congenital stationary night blindness (CSNB) are unable to distinguish objects in dim-light conditions. This impairment presents challenges, especially where artificial lighting is unavailable or when
    driving at night.


    ==========================================================================
    In 2015, researchers from Penn's School of Veterinary Medicine learned
    that dogs could develop a form of inherited night blindness with strong similarities to the condition in people. In 2019, the team identified
    the gene responsible.

    Today, in the journal Proceedings of the National Academy of Sciences,
    they've reported a major advance: a gene therapy that returns night vision
    to dogs born with CSNB. The success of this approach, which targets
    a group of cells deep in the retina called ON bipolar cells, charts a significant step toward a goal of developing a treatment for both dogs
    and people with this condition, as well as other vision problems that
    involve ON bipolar cell function.

    Dogs with CSNB that received a single injection of the gene therapy began
    to express the healthy LRIT3 protein in their retinas and were able to
    ably navigate a maze in dim light. The treatment also appears lasting,
    with a sustained therapeutic effect lasting a year or longer.

    "The results of this pilot study are very promising," says Keiko
    Miyadera, lead author on the study and an assistant professor at Penn
    Vet. "In people and dogs with congenital stationary night blindness,
    the severity of disease is consistent and unchanged throughout their
    lives. And we were able to treat these dogs as adults, between 1 and 3
    years of age. That makes these findings promising and relevant to the
    human patient population, as we could theoretically intervene even in
    adulthood and see an improvement in night vision." In the earlier work,
    the Penn Vet team, working in collaboration with groups from Japan,
    Germany, and the United States, discovered a population of dogs with
    CSNB and determined that mutations in the LRIT3 gene were responsible
    for the dogs' night vision impairment. The same gene has been implicated
    in certain cases of human CSNB as well.



    ==========================================================================
    This mutation affects the ON bipolar cells' function, but, unlike in
    some blinding diseases, the overall structure of the retina as a whole
    remained intact. That gave the research team hope that supplying a normal
    copy of the LRIT3 gene could restore night vision to affected dogs.

    Yet while Penn Vet researchers from the Division of Experimental Retinal Therapies have developed effective gene therapies for a variety of other blinding disorders, none of these earlier treatments has targeted the
    ON bipolar cells, located deep within the middle layer of the retina.

    "We've stepped into the no-man's land of the retina with this gene
    therapy," says William A. Beltran, a coauthor and professor at Penn
    Vet. "This opens the door to treating other diseases that impact the ON
    bipolar cells." The researchers overcame the hurdle of targeting these relatively inaccessible cells with two key findings. First, through a
    rigorous screening process conducted in collaboration with colleagues
    at the University of California, Berkeley, led by John Flannery and
    at the University of Pittsburgh led by Leah Byrne, they identified a
    vector for the healthy LRIT3 gene that would enable the treatment to
    reach the intended cells. And, second, they paired the healthy gene with
    a promoter -- the genetic sequence that helps initiate the "reading"
    of the therapeutic gene -- that would act in a cell-specific fashion.

    "Prior therapies we've worked on have targeted photoreceptors or retinal pigment epithelium cells," says coauthor Gustavo D. Aguirre, a Penn Vet professor. "But the promoter we use here is very specific in targeting
    the ON bipolar cells, which helps avoid potential off-target effects
    and toxicity." The researchers suspect that restoring the functional
    LRIT3 gene enables signals to cross from the photoreceptor cells to the ON bipolar cells. "LRIT3 is expressed at the 'finger' tips of these cells,"
    says Beltran. "Introducing this transgene is essentially allowing the
    two cells to shake hands and communicate again."


    ==========================================================================
    An open question is whether targeting both photoreceptor cells and
    ON bipolar cells together could lead to even greater improvements in
    night vision. Other research groups studying these conditions in mice
    have targeted the therapy to photoreceptor cells and found some vision
    to be restored, suggesting a possible path to enhance the effects of
    gene therapy.

    And while the therapy enabled functional recovery -- dogs were able to
    navigate a maze when their treated eye was uncovered but not when it was covered -- the healthy copy of the gene was only expressed as much as 30%
    of ON bipolar cells.

    In follow-up work, the researchers hope to augment this uptake.

    "We had great success in this study, but we saw some dogs get better
    recovery than others," says Miyadera. "We'd like to continue working
    to maximize the therapeutic benefit while still ensuring safety. And
    we've seen that this treatment is durable, but is it lifelong after
    one injection? That's something we'd like to find out." The team also
    plans to amend the therapy to use the human version of the LRIT3gene,
    a necessary step toward translating the treatment to people with CSNB
    with an eventual clinical trial.

    Miyadera, Beltran, and Aguirre coauthored the study with Penn Vet's
    Evelyn Santana, Karolina Roszak, Sommer Iffrig, Yu Sato, Alexa Gray,
    Ana Ripolles Garcia, and Valerie Dufour; Charles River Laboratories'
    Simone Iwabe, Ryan F.

    Boyd, and, Joshua T. Bartoe; and the University of California, Berkeley's
    Meike Visel, John G. Flannery, and Leah C. Byrne (now at the University
    of Pittsburgh).

    Keiko Miyadera is an assistant professor of ophthalmology in Penn Vet's Department of Clinical Sciences & Advanced Medicine.

    William Beltran is a professor of ophthalmology in Penn Vet's Department
    of Clinical Sciences & Advanced Medicine and director of theDivision of Experimental Retinal Therapies.

    Gustavo D. Aguirre is a professor of medical genetics and ophthalmology
    in Penn Vet's Department of Clinical Sciences & Advanced Medicine.

    The study was supported by the Margaret Q. Landenberger Research
    Foundation, National Eye Institute/National Institute of Health (Grant EY-006855), Foundation Fighting Blindness, Van Sloun Foundation for
    Canine Genetic Research, and Sanford and Susan Greenberg End Blindness Outstanding Achievement Prize.


    ========================================================================== Story Source: Materials provided by University_of_Pennsylvania. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Keiko Miyadera, Evelyn Santana, Karolina Roszak, Sommer Iffrig,
    Meike
    Visel, Simone Iwabe, Ryan F. Boyd, Joshua T. Bartoe, Yu Sato, Alexa
    Gray, Ana Ripolles-Garcia, Vale'rie L. Dufour, Leah C. Byrne, John
    G. Flannery, William A. Beltran, Gustavo D. Aguirre. Targeting
    ON-bipolar cells by AAV gene therapy stably reverses LRIT3
    -congenital stationary night blindness. Proceedings of the National
    Academy of Sciences, 2022; 119 (13) DOI: 10.1073/pnas.2117038119 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220322191209.htm

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