|University of Pennsylvania, Philadelphi|
|Stop codon read-through|
|Human trials in DMD expected this year|
Muscle biology was mainly an intellectual curiosity for Lee Sweeney when he first set up his University of Pennsylvania research laboratory. His perspective changed as he got to know people who had Duchenne MD.
“I started giving talks in front of some of the parents and going to meetings where I actually had some interaction with some of the patients and their families. And, you know, it put a human side on what to me had been just sort of an esoteric disease,” he says. “At that point I decided that I really needed to try to work on therapeutics.”
Sweeney, chairman of the Physiology Department at Penn, is a member of the Scientific Advisory Board of the biotechnology company PTC Therapeutics, which is developing a new drug that he thinks could treat as many as 10 percent to 15 percent of those with DMD. The drug, dubbed PTC124, targets premature stop codons and may also work in other forms of muscular dystrophy, as well as for certain other genetic disorders, such as hemophilia and cystic fibrosis.
For years, molecular biologists have been trying to replace faulty genes with working versions. Unfortunately, says Sweeney, “We can’t replace a gene at this point in time.” (Human trials to do so in DMD are expected to begin next year.)
A more pragmatic approach than traditional gene therapy, he says, might be to coax the faulty gene into making a protein that works. That’s what PTC124 does to genes with premature stop codons.
PTC124 sticks to ribosomes — the cells’ protein factories — and prompts them to interpret a premature stop codon as a normal codon. Instead of aborting assembly of the protein, the ribosome inserts a protein building block — an amino acid — and continues making a complete protein chain until it encounters the normal termination codon, which the ribosome correctly interprets as a stop.
Based on results from preclinical studies in animals and cultured cells, Sweeney is optimistic about using PTC124 to treat boys with DMD who have premature stop codons in their dystrophin genes.
When lab mice with a premature stop codon in the dystrophin gene were given the drug, their dystrophin protein levels reached 25 percent of those of healthy mice, and their disease stabilized. And, Sweeney points out, “our mouse model is almost a worst case.”
|Elisabeth Barton and H.Lee Sweeney at the University of Pennsylvania are studying Duchenne MD in mice with hopes of developing treatments. Photo by Addison Geary|
The dystrophin-deficient mice have a very early premature stop codon, and, the earlier the premature stop codon occurs in a gene, the more difficult it can be to correct. Sweeney speculates that in humans “maybe 20 percent [of normal dystrophin protein levels] would lead to sort of a mild disease, and 50 percent would probably be enough to eradicate the disease.”
In January, the U.S. Food and Drug Administration awarded Orphan Drug designation, a set of financial incentives to encourage pharmaceutical companies to develop drugs for rare diseases, to PTC Therapeutics, for PTC124 development. Phase 1 clinical trials of PTC124 in healthy people, which concluded last year, show promising results. Humans don’t break down the drug nearly as fast as mice, which should make it much easier to administer effective doses.
A new phase 1 trial using multiple dosage levels of PTC124 began this year, and Sweeney anticipates that phase 2 clinical trials in boys with DMD will begin this spring or summer, if regulatory approvals are obtained.
“I’m incredibly hopeful that this is going to work in some of the patients, maybe stabilize or at least slow [DMD progression] in some and maybe even stop the disease in others,” Sweeney says. “And so, I’m just anxious to start treating people. I’m very excited about it.”