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New Drug Bypasses Gene Mutations

A compound that helps cells produce normal proteins from wonky genes could have a broad impact on genetic diseases.
November 14, 2008

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.

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.

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.

Patients with cystic fibrosis lack a protein called CFTR (cystic fibrosis transmembrane regulator), which is involved in the transport of chloride ions in and out of cells. Without this protein, thick mucus clogs the lungs, eventually leading to respiratory failure. Scientists found that patients given the drug showed protein production in the nasal epithelium, which is similar to the lung epithelium. Patients also wore vests studded with sensors, which indicated a 30 percent reduction in coughing: people with cystic fibrosis cough an average of 600 to 1,500 times a day, compared with two or three times for healthy people. However, neither study was blinded, meaning that both scientists and patients knew who was getting the drug.

A larger, placebo-controlled study of the drug’s effectiveness against muscular dystrophy is now under way, with 175 patients at 38 sites in the United States, Europe, Australia, and Israel. A similar study for cystic fibrosis will begin next year. The tests will last a year or more, allowing scientists to determine whether, over time, the drug can boost protein production enough to halt the progression of the diseases. (Even though scientists measured changes in some symptoms in the earlier studies, they were not designed to determine how effective the drug was at treating patients, but rather whether the target proteins were made.) Lee Sweeney, a biologist at the University of Pennsylvania who collaborates with PTC, estimates from animal research that protein production will need to rise to about 20 to 30 percent of normal levels. “We will get insight over the next six months into how much we can halt their disease,” he says.

The trials will also be an important test of safety. While no safety problems have yet arisen in human studies, the long-term effects of the drug are not yet clear. “I do worry a bit about off-target effects,” says Melissa Spencer, a researcher at the DMD research center at the University of California, Los Angeles, who is not involved with PTC. Because the drug allows protein-production machinery to skip over premature stop signs, there have been concerns that it might skip normal protein termination signals as well, producing extralong proteins. PTC says that so far it has seen no signs of this.

The drug has also shown promise in animal models of other diseases, including Rett syndrome, some tumors with mutations in tumor suppressor genes, and hemophilia, says Stuart Peltz, PTC’s chief executive officer. The company is now planning human tests of the drug for hemophilia A and B, he says.

Because the compound is a small molecule that can be taken orally, it has some advantages over other new biological therapies being developed to treat these diseases, including gene therapy and RNA interference. Such therapies are often difficult to deliver and can trigger immune reactions. “It’s essentially a gene therapy that is using cellular machinery rather than introducing DNA,” says Spencer. “The chance of immune response is much less than if you took a virus and put it in that way.”

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