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First demonstration of muscle restoration in an animal model of Duchenne muscular dystrophy
April 23, 2007Implications for treating many types of genetic diseases
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 of Nature.
"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 breathing muscles.
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 proteins.
"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.
University of Pennsylvania School of Medicine
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 breathing muscles.
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 proteins.
"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.
University of Pennsylvania School of Medicine
Muscular Dystrophy Current Events and Muscular Dystrophy News RSSMU logo News Bureau University of Missouri About the News Bureau Contact Us Home / News Releases / 2009 MU Researchers Discover Target that Could Ease Spinal Muscular Atrophy Symptoms
There is no cure for spinal muscular atrophy (SMA), a genetic disorder that causes the weakening of muscles and is the leading genetic cause of infant death, but University of Missouri researchers have discovered a new therapeutic target that improves deteriorating skeletal muscle tissue caused by SMA. The new therapy enhanced muscle strength, improved gross motor skills and increased the lifespan in a SMA model.
Lamin A/C deficiency is 'unnerving'
Mutations in the nuclear intermediate filament lamin A/C (LMNA) gene are associated with Emery-Dreifuss muscular dystrophy, but cause the disease by unknown mechanisms. Méjat et al. show that one mechanism involves the disruption of neuromuscular junctions.
Potential therapy for congenital muscular dystrophy
Current research suggests laminin, a protein that helps cells stick together, may lead to enhanced muscle repair in muscular dystrophy.
New insight into the controls on a go-to enzyme
Scientists at St. Jude Children's Research Hospital have gained new insights into regulation of one of the body's enzyme workhorses called calpains.
Scientists exploring new compounds to target muscular dystrophy
Scientists have identified a promising set of new compounds in the fight against muscular dystrophy.
Scientist clears hurdles for muscular dystrophy therapy
Approximately 250,000 people in the United States have some form of muscular dystrophy. Duchenne muscular dystrophy (DMD) is the most common type of the disease, predominantly affecting males.
Study may explain exercise-induced fatigue in muscular dystrophies
A University of Iowa study suggests that the prolonged fatigue after mild exercise that occurs in people with many forms of muscular dystrophy is distinct from the inherent muscle weakness caused by the disease.
Mediator in communication between neurons and muscle cells found
A missing piece of the puzzle of how neurons and muscle cells establish lifelong communication has been found by researchers who suspect this piece may be mutated and/or attacked in muscular dystrophy.
Study finds value in 'junk' DNA
For about 15 years, scientists have known that certain "junk" DNA -- repetitive DNA segments previously thought to have no function -- could evolve into exons, which are the building blocks for protein-coding genes in higher organisms like animals and plants.
PTC124 shows activity in cystic fibrosis; Phase 2 proof-of-concept data published in Lancet
New phase 2 data published today in The Lancet show that the investigational oral drug PTC124 demonstrates activity in nonsense-mutation cystic fibrosis (CF). The data show that treatment with PTC124 results in statistically significant improvements in the chloride channel function of patients with nonsense-mutation CF. The study was conducted at the Hadassah Hebrew University Hospital in Jerusalem, Israel and sponsored by PTC Therapeutics (PTC).
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