New Drug May Treat Cystic Fibrosis, Other Diseases Caused by “Nonsense Mutations"

Bedwell is a renowned researcher on the select group of genetic alterations called nonsense mutations – DNA alterations that can lead to nonfunctional or missing proteins. He presented recent findings on an experimental drug that may help to treat some cystic fibrosis patients during the Experimental Biology 2010 conference in Anaheim, Calif., April 26. This drug ataluren (formerly called PTC124) also holds promise in treating more than 2,400 different genetic disorders caused by nonsense mutations.

“When you treat a genetic disease, the bottom line is how much of the missing protein do you need to restore to have a therapeutic benefit,” Bedwell says. “It comes down to the threshold of protein rescue. For some diseases, it might be 1 percent of protein you need restored, and for other diseases you may need 50 percent of protein restored.”

In Bedwell's most well-known study, ataluren restored up to 29 percent of normal protein function in mice with cystic fibrosis. Another researcher not affiliated with UAB has reported ataluren restored up to 25 percent of the missing or abnormal protein function in mice with Duchenne muscular dystrophy.

An estimated one-third of gene defects responsible for human disease are thought to come from nonsense mutations. In the case of cystic fibrosis, the absence of a certain protein leads to an imbalance of salt and water in the linings of the lungs and other membranes. The UAB study showed that ataluren allowed the protein to be made in mouse cells where it was previously absent, and it helped the body's regulatory system to restore salt and water balance in the membrane.

Bedwell says the true promise of drugs that suppress nonsense mutations is their selectiveness, meaning the drugs work well in fixing disease-causing mutations while generally sparing healthy genes.

Ataluren is now being tested in humans for its effectiveness in treating Duchenne/Becker muscular dystrophy, cystic fibrosis, hemophilia A, hemophilia B and other conditions. The agent works in an oral form.

The research is a partnership with Bedwell and UAB's Gregory Fleming James Cystic Fibrosis Research Center. It is funded by PTC Therapeutics Inc. with assistance from the National Institutes of Health.

Editor's Note: Bedwell reports a consulting relationship with ataluren-maker PTC Therapeutics.

About the UAB Department of Microbiology

Known for its innovative and interdisciplinary approach to research, training and education, the UAB Department of Microbiology is a world leader in microbial genetics, pathogenesis, immunology and virology.

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