Drug may cure genetic diseases
An experimental drug can effectively cure Duchenne muscular dystrophy in mice by correcting a genetic defect and allowing healthy muscles to develop, researchers reported Sunday in a paper published online by the journal Nature.
Preliminary studies in humans with muscular dystrophy and cystic fibrosis suggest the drug is safe, well-tolerated and potentially effective, according to a team headed by H. Lee Sweeney, chairman of physiology at the University of Pennsylvania School of Medicine.
In addition to Duchenne muscular dystrophy -- a prevalent, rapidly worsening form of the disorder -- the drug has the potential to cure a host of genetic diseases caused by the same mutation, Sweeney said.
“There are literally thousands of genetic diseases that could benefit from this approach,” he said. “What’s unique about this drug is it doesn’t just target one mutation that causes disease, but a whole class of mutations.”
The mutations are called premature termination codons, or PTCs. These mutations tell the cell’s protein-making machinery to stop synthesis before a protein is completely assembled. In the case of muscular dystrophy, the mutated gene -- which is present in about 15% of MD patients -- leads to the production of a truncated form of dystrophin, a crucial protein that helps keep muscle cells intact.
About 10 years ago, Sweeney discovered that the antibiotic gentamicin could override PTCs to allow production of intact proteins like dystrophin. But it required high concentrations of the drug, which produced severe side effects.
His team subsequently screened more than 800,000 compounds until they found the current candidate, called PTC124. This drug overrides the mutated termination codon, but not the normal stop codon at the end of the gene. It is produced by PTC Therapeutics of South Plainfield, N.J. Sweeney is a member of the company’s scientific advisory board.
In the new study, his team administered the drug to so-called mdx mice, which carry the premature termination codon. Within two to eight weeks, the researchers detected full-length dystrophin in the animals. Although it was produced at low levels, it was enough to produce healthy muscles.
“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,” Sweeney said.
The new findings indicate that “there is now hope that PTC124 ... could be more beneficial in the clinic” than gentamicin, German researchers wrote in an accompanying editorial.
The research was sponsored by the National Institutes of Health, the Muscular Dystrophy Assn. and Parent Project Muscular Dystrophy.
PTC Therapeutics is conducting trials in muscular dystrophy patients in the United States and in cystic fibrosis patients in the U.S. and Israel.
Preliminary results reported by the company last year indicated boys receiving the treatment for MD had greater activity and increased endurance.
The cystic fibrosis patients showed decreased sputum volume and thickness, decreased frequency and severity of coughing, and a better sense of wellbeing, the company said.
