||Researchers at the University
of Pennsylvania School of Medicine, along with
colleagues at PTC Therapeutics Inc. and the University
of Massachusetts Medical School, have for the first time
demonstrated restoration of muscle function in a mouse
model of Duchenne's muscular dystrophy (DMD).
||In DMD, patients are missing dystrophin,
a protein that helps keep muscle cells intact.
||The new drug attaches to ribosomes in
all cell types within the MD mouse model, overriding the
mutation in the dystrophin gene that tells it to halt production
of the protein. Instead of stopping, the full-length dystrophin
protein is made.
||The research appears ahead of print in
an advanced online publication of Nature.
(PHILADELPHIA) – Using a new type of drug that targets a
specific genetic defect, researchers at the University
of Pennsylvania School of Medicine, along with colleagues
at PTC Therapeutics Inc. and the University
of Massachusetts Medical School, have for the first time demonstrated restoration of muscle function in a mouse model of Duchenne's
muscular dystrophy (DMD).
The research appears ahead of print in an advanced online publication
Dr. Sweeney directs a Paul
Wellstone Muscular Dystrophy Cooperative Center,
sponsored by the National Institute
of Arthritis and Musculoskeletal and Skin Diseases. He is also on the Scientific
Advisory Board of PTC Therapeutics
“This new class of treatment has the potential to help a large number of
patients with different genetic diseases that have the same type of mutation,” says
senior author H. Lee Sweeney, PhD, chair of the Department
of Physiology at Penn. This genetic flaw causes from 5 to 15 percent (and in a few
instances up to 70 percent) of individual cases of most inherited diseases, including
DMD, cystic fibrosis, and hemophilia.
The new drug, developed by the South Plainfield, NJ-biotech firm and called
PTC124, binds to the ribosome, a cellular component where the genetic code is
translated into proteins, one amino
acid at a time. The drug allows the ribosome
to read through a mistake in the genetic code called a premature stop codon in
order to properly make whole proteins.
In DMD, patients are missing dystrophin, a protein that helps keep muscle cells
intact. About 15 percent of DMD patients do not make dystrophin because of the
mutation. DMD eventually affects all voluntary muscles, as well as heart and
PTC124 attaches to ribosomes in all cell types within the MD mouse model, overriding
the mutation in the dystrophin gene that tells it to halt production of the protein.
Instead of stopping, the full-length dystrophin protein is made. The drug
enables enough protein to be made to correct defects in the muscle of the DMD
mouse, and at the same time the drug does not prevent the ribosome from reading
correct “stop” signals in the genetic code to make other necessary
“Enough dystrophin accumulated in the muscles of the MD mice so that we
could no longer find defects in the muscles when we examined them,” says
Sweeney. “For all intents and purposes the disease was corrected by treatment
with PTC124.” The drug allowed dystrophin to be made in cells in which
it was previously absent, to be delivered to the proper location at the cell
membrane, and to induce restoration of muscle function in rodent muscles.
Co-first author Elisabeth Barton, PhD, worked on this project
as a postdoctoral fellow in the Sweeney lab, and continued as a collaborator
when she became an Assistant Professor in Penn’s School
of Dental Medicine.
The study was supported in part by the Muscular
Dystrophy Association and the
Parent Project Muscular Dystrophy.
PTC124 is presently nearing the end of a Phase
II multi-center clinical trial in DMD
patients, of which Children's Hospital of Philadelphia is a major accruing site.
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