Researchers demonstrate new approach to treating muscular dystrophy

Published on February 12, 2014 at 12:59 AM · No Comments

Researchers at Washington University School of Medicine in St. Louis have demonstrated a new approach to treating muscular dystrophy. Mice with a form of this muscle-weakening disease showed improved strength and heart function when treated with nanoparticles loaded with rapamycin, an immunosuppressive drug recently found to improve recycling of cellular waste.

The study appears online in The FASEB Journal.

The investigators, including first author Kristin P. Bibee, MD, PhD, looked at a mouse model of Duchenne muscular dystrophy, the most severe inherited form of the disease. Duchenne exclusively affects boys who have to rely on wheelchairs by age 12 and die from heart or respiratory failure in their 20s.

The faulty gene that causes the disease prevents the body from producing dystrophin, a protein crucial for maintaining muscle cell integrity and function. The new study demonstrated that mice with muscular dystrophy, in addition to missing dystrophin, also can't recycle cellular waste, a process known as autophagy, or self-eating.

"Autophagy plays a major role in disposing of cellular debris," said senior author Samuel A. Wickline, MD, the James R. Hornsby Family Professor of Medicine. "If it doesn't happen, you might say the cell chokes on its own refuse. In muscular dystrophy, defective autophagy is not necessarily a primary source of muscle weakness, but it clearly becomes a problem over time. If you solve that, you can help the situation by maintaining more normal cellular function."

Though it's not clear how the missing dystrophin protein might be responsible for the muscle cells' poor housekeeping, the study showed that boosting autophagy improved skeletal muscle strength and heart function in these mice.

"Some investigators are looking for ways to replace dystrophin," said co-author Conrad C. Weihl, MD, PhD, associate professor of neurology. "But here we are focusing on the defect in autophagy. What is exciting about our approach is that there are existing drugs that activate autophagy. And by repackaging the drug on nanoparticles, we can target it specifically to muscles and correct the defect in the cells' ability to recycle waste."

When treated with rapamycin nanoparticles, the mice showed a 30 percent increase in grip strength and a significant improvement in cardiac function, based on an increase in the volume of blood the heart pumped.

"An important aspect of our study is that we are treating both skeletal muscle and heart muscle with the same drug," Wickline said. "The heart is a difficult organ to treat in muscular dystrophy. But even in older animals, this regimen works well to recover heart function, and it is effective over a short period of time and after only a few doses."

"Death from Duchenne in many people is due to heart dysfunction," said Weihl, who also treats patients with neuromuscular disorders at Barnes-Jewish Hospital. "So even improving cardiac function by 10 percent in late-stage disease could be very important."

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