New Drug Bypasses Gene Mutations

A compound that helps cells produce normal proteins from wonky genes could have a broad impact on genetic diseases.

A novel drug that enables the production of normal proteins from mutated DNA might one day help people with a variety of genetic diseases. The drug has shown promise as a treatment for cystic fibrosis and muscular dystrophy, and it is now being tested in large, international clinical trials.

Missing pieces: A novel drug developed by PTC Therapeutics allows diseased cells to produce cystic fibrosis transmembrane regulator (CFTR), a protein missing in cystic fibrosis patients. Intestinal cells of an untreated rodent are shown at top; those of a treated animal, with the CFTR protein labeled in red, are at bottom. Credit: PTC Therapeutics

Most drugs alter the activity of proteins after they're manufactured, but the new drug intervenes in the cellular machinery that makes the proteins in the first place. Consequently, it could be effective against diseases where completely different proteins go awry. "It's a great breakthrough," says Robert Singer, a biologist at the Albert Einstein Medical School, in New York, who is not involved with the company that produces the drug.

Severe genetic disorders, such as muscular dystrophy, result from mutations in genes that code for vital proteins. In some cases, the mutation is a misplaced genetic stop sign, a sequence that tells the cellular machinery to halt production before the protein is complete. The result can be a truncated, ineffective version of the protein, or none at all. The new drug, being developed by PTC Therapeutics, a startup in South Plainfield, NJ, allows the cellular machinery to essentially skip over these aberrant stop signs and produce normal molecules.

While severe genetic diseases are individually rare, mutations that prematurely truncate protein production are found in many of them--including spinal muscular atrophy, hemophilia, and retinitis pigmentosa. "Since the drug treats the underlying gene-expression problem, it is applicable to a few thousand diseases," says Allan Jacobson, chair of the department of Molecular Genetics and Microbiology at the University of Massachusetts Medical School, in Worcester, and a PTC cofounder.

PTC is focusing its early clinical efforts on Duchenne muscular dystrophy (DMD), a degenerative muscle disease that affects approximately 20,000 children a year worldwide (one of every 3,500 male children), and cystic fibrosis, a chronic disease of the lungs and digestive system that affects about 70,000 people worldwide. About 15 percent of DMD cases result from premature stop signs. For cystic fibrosis, the number is about 10 percent worldwide, but more than 50 percent in Israel. No drugs have been approved to treat DMD, and the drugs approved for cystic fibrosis treat its symptoms rather than its cause.

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Results from early clinical tests for both diseases, which wrapped up last year, were "incredibly encouraging," says Brenda Wong, a neurologist at the Cincinnati Children's Hospital Medical Center, who led part of the trial.

Muscle biopsies showed that about 50 percent of DMD patients taking the drug began making normal copies of the dystrophin protein--a structural protein that helps maintain muscle's tensile strength. Without this protein, muscles are fragile and break down over time.