Researchers from South Plainfield, N.J., biotechnology company PTC Therapeutics Inc. and their collaborators from the University of Pennsylvania and the University of Massachusetts reported new findings about PTC124, which is in Phase II clinical trials, in the April 20, 2007 early online edition of Nature.

The drug targets so-called nonsense mutations, in which a mutation changes a protein's DNA sequence to include an early stop codon. That in turn leads to the transcription machinery's abandoning the half-finished protein. In most genetic disorders, mutations that add a premature stop codon account for 5 percent to 15 percent of cases, though the number can exceed 60 percent in some diseases and some subpopulations.

Because such truncated proteins tend to monkey wrench cellular functioning, cells have evolved "a surveillance pathway that recognizes, quite selectively, premature termination codons," PTC Therapeutics CEO Stuart Peltz told BioWorld Today. As a result, proteins with an early stop codon are transcribed, but then rapidly degraded by the surveillance pathway, which is able to recognize that the truncated RNA lacks key features of a normal transcript.

PTC124 interacts with that surveillance pathway, which is also the reason the drug does not lead to the extension of normal proteins beyond their stop codons.

In the Nature paper, the researchers focused on Duchenne's muscular dystrophy (DMD). In Duchenne's, which is the most common inherited fatal neuromuscular disorder, lack of the protein dystrophin leads to a weakening of muscle cell membranes and consequently, loss of strength by about age 5. Few of the afflicted live past their early 30s.

The scientists tested PTC124 in both human and mouse cells and found that the compound partially restored dystrophin to those cells. While the levels of dystrophin were still lower then in wild-type mice, they were sufficient to restore muscle function. In mice treated with a combination of orally administered and injected PTC124 for several weeks, dystrophin levels were sufficiently high to prevent the muscle injuries that occur when the Duchenne's muscles are repeatedly tasked.

PTC124 is in separate Phase II clinical trials for the treatment of both Duchenne's muscular dystrophy and cystic fibrosis. Peltz said that "we believe we have proof of principle of activity" for both diseases.

The survival statistics for cystic fibrosis patients are similarly bleak to those of DMD, though the mechanism is a different one. In it, a nonfunctional channel blocks movement of chloride ions in airway epithelial cells, meaning that the mucus that coats the lungs cannot be kept moist by normal osmotic processes. As a result, patients become prone to bacterial infections.

But premature stop codons are a common underlying cause of diseases ranging far beyond Duchenne's and cystic fibrosis - PTC, the company said, "has cataloged over 1,800 distinct genetic disorders where nonsense mutations are the cause of the disease in a significant percentage of patients."

For that reason, if it pans out, PTC124 could turn into the equivalent of a broad-spectrum antibiotic for genetic disorders. "We think it could potentially be applicable in many, many diseases," Peltz said.

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