• An approach to treating a severe congeni

    From ScienceDaily@1:317/3 to All on Tue Mar 29 22:30:40 2022
    An approach to treating a severe congenital myopathy

    Date:
    March 29, 2022
    Source:
    University of Basel
    Summary:
    The diagnosis is rare, but devastating -- children with congenital
    muscle disorders often never learn to walk. Until now, there was no
    chance of recovery, but researchers are now presenting a possible
    therapeutic approach.



    FULL STORY ==========================================================================
    The diagnosis is rare, but devastating -- children with congenital muscle disorders often never learn to walk. Until now, there was no chance
    of recovery, but researchers at the University of Basel and University
    Hospital Basel are now presenting a possible therapeutic approach for
    the first time.


    ========================================================================== Professor Susan Treves remembers seeing one child affected by
    the condition at the age of six months. The boy seemed more like
    a newborn, she recalls. Today, several years later and thanks to
    intensive physiotherapy, he is at least able sit. "He made it," says the researcher. There is as yet no cure for children like this one. Their
    first priority is survival. Another child with mutations in the same
    gene as the boy mentioned above, did not survive. However, his genetic alterations now form the basis of a therapeutic approach presented by
    the research group led by Susan Treves and Professor Francesco Zorzato
    in the scientific journal eLife.

    The affected gene contains the blueprint for a calcium channel called
    RYR1 in skeletal muscle. The mutations render the gene useless, and
    this has severe consequences for muscle function. The researchers used
    the gene alterations found in a patient, as a template to develop a
    mouse model for this type of congenital myopathy. "The mice don't die,
    but their muscle system is severely impaired," says Treves. "They're
    smaller, and move much less." With a combination of two drugs, however,
    the research team was able to significantly improve muscle function and movement of the mice.

    Genetic material overload The therapy is based on the observation that
    certain enzymes are produced in excessive quantities in the skeletal
    muscles of affected patients. These enzymes -- histone deacetylases
    and DNA methyltransferases, to be specific - - affect the density of the packaging of the genetic material. This makes genes less accessible to the cellular machinery that reads them and translates them into instructions
    for protein production.

    Treves and her team used inhibitors against these enzymes, which
    are already approved as cancer drugs or are being tested in clinical
    trials. The treatment brought about a significant improvement in the
    ability of the mice to move, although they remained smaller than healthy animals from the same litter.

    Importantly, the researchers did not observe any adverse side effects
    during the study period.

    From gene to therapy The approach is still far from being a clinically applicable therapy, says Treves. "But it's a first step in the right direction." In their next step, the researchers aim to further optimize
    the treatment and test combinations of newly developed drugs targeting
    the same enzymes to achieve even better effects. "We anticipate around
    about two more years of optimization and testing before we can initiate
    a phase I clinical trial," she says.

    For Susan Treves and Francesco Zorzato, these first promising results
    represent a milestone victory after more than 10 years of research -- especially as Zorzato was the one who first isolated the gene affected in
    these muscle disorders years ago. "We've now succeeded in bridging the
    gap from the isolation of the affected gene to a therapeutic approach,"
    says Treves.


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


    ========================================================================== Journal Reference:
    1. Alexis Ruiz, Sofia Benucci, Urs Duthaler, Christoph Bachmann,
    Martina
    Franchini, Faiza Noreen, Laura Pietrangelo, Feliciano Protasi,
    Susan Treves, Francesco Zorzato. Improvement of muscle strength
    in a mouse model for congenital myopathy treated with HDAC
    and DNA methyltransferase inhibitors. eLife, 2022; 11 DOI:
    10.7554/eLife.73718 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220329100013.htm

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