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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