||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
“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.
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
of PTC Therapeutics
PENN Medicine is a $2.9 billion enterprise
dedicated to the related missions of medical education, biomedical
research, and high-quality patient care. PENN Medicine consists
of the University of Pennsylvania School of Medicine (founded in
1765 as the nation's first medical school) and the University of
Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt
of NIH research funds; and ranked #3 in the nation in U.S. News
& World Report's most recent ranking of top research-oriented
medical schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its superior
education and training of the next generation of physician-scientists
and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals,
all of which have received numerous national patient-care honors [Hospital
of the University of Pennsylvania; Pennsylvania Hospital, the nation's
first hospital; and Penn Presbyterian Medical Center]; a faculty practice
plan; a primary-care provider network; two multispecialty satellite
facilities; and home care and hospice.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.