Possible New Treatment Target Found for Muscular Dystrophy (5/16/2007)

Scientists have identified a potential therapeutic target in muscles for the treatment of Duchenne muscular dystrophy, the most common form of the progressive disease.

The researchers focused on the role of a protein involved in the body's inflammatory response named nuclear factor kappa B (NF-kB). The study confirmed that this protein is responsible for the chronic inflammation and muscle-cell death that are hallmarks of Duchenne muscular dystrophy.

The research also showed that activation of the protein is required to block the ability of skeletal muscle cells to regenerate the cells destroyed by that very same inflammation.

This dual role makes the protein particularly attractive as a target for therapy, said Denis Guttridge, assistant professor of molecular virology, immunology and medical genetics at Ohio State University Medical Center and senior author of the research.

"NF-kB is driving the inflammation – but that's only half of the story. It also plays a role in skeletal muscle cells by blocking their ability to regenerate," said Guttridge, also a researcher in Ohio State's human cancer genetics program.

Guttridge and his colleagues also found that inhibiting the protein reduced inflammation and allowed muscle tissue to regenerate in animals with a disease similar to muscular dystrophy, suggesting that a drug against NF-kB could one day serve as therapy to prevent progression of the disease in humans.

The work was published in the April issue of the Journal of Clinical Investigation.

Duchenne muscular dystrophy affects about one in 3,500 boys, who show early symptoms of muscle degeneration and typically lose the ability to walk between age 6 and 12. With progressive disease, most patients die of respiratory failure or cardiac dysfunction in their 20s. Girls can carry the gene that causes the disease, but most have no symptoms.

In muscular dystrophy, the immune system attacks muscle cells, which causes cell death. The muscle tissue can regenerate because stem cells replenish them when the muscle is injured. But, in general, humans have a limited pool of muscle stem cells. Researchers believe that the constant action of muscle degeneration and regeneration eventually expends all available stem cells, tipping the balance toward progressive muscle degeneration.

Previous research has shown that the immune process becomes heightened in muscular dystrophy, contributing to chronic inflammation that kills muscle cells. NF-kB is implicated in that process, suggesting that blocking the protein should stop the inflammation. But to date, anti-inflammatory medications used to treat Duchenne muscular dystrophy do not appear to be effective in slowing progression of the disease.

So Guttridge and colleagues took that theory a step further, demonstrating that the process that activates NF-kB also affects muscle cells' ability to regenerate. The researchers used mice lacking the dystrophin gene, which is essential for the structure, function and integrity of muscles. Mutations in the dystrophin gene are the primary cause of Duchenne muscular dystrophy.

When the researchers raised mice that also lacked I-kappa-b kinase (IKK), the enzyme that turns on the NF-kB protein, they found a noticeable increase in cell regeneration in muscles of mice carrying the disease that mimics Duchenne muscular dystrophy.

Guttridge and his colleagues then used a chemical inhibitor to block the protein's activation. They introduced an experimental peptide, engineered to block the enzyme's activation of the protein, into muscles of mice lacking the dystrophin gene.

"Blocking NF-kB led to improved muscle function," Guttridge said. "Validating the role of this protein in disease progression with a drug-based inhibitor suggests that NF-kB is a viable target in this disease."

Guttridge said any drug developed to block NF-kB might slow the degeneration-regeneration cycles in Duchenne muscular dystrophy patients or might even reduce the initial inflammation, which would delay onset of that cyclical process.

The researchers plan to conduct additional studies of the peptide under different conditions before trying to prove its usefulness for clinical application in humans.

The compound, known as a NEMO-binding domain peptide, was discovered at Yale University and developed by TheraLogics Inc., a North Carolina-based company.

This research was supported by the National Cancer Institute and the Muscular Dystrophy Association.

Ohio State co-authors are graduate student Swarnali Acharyya (lead author), with graduate student Nadine Bakkar, research scientist Micheal Carathers and associate professor Michael Weinstein of the human cancer genetics program; postdoctoral researcher Tepmanas Bupha-Intr and assistant professor Paul M. L. Janssen of physiology and cell biology; professor Zarife Sahenk of neurology; and graduate student Katherine L. Gardner and associate professor Jill A. Rafael-Fortney of molecular and cellular biochemistry.

Note: This story has been adapted from a news release issued by the Ohio State University Medical Center

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