DMD/BMD Reseach: Minidystrophin Gene

A promising “minidystrophin gene” that restores normal muscle force to skeletal and diaphragm muscles in mice with a disease resembling Duchenne muscular dystrophy (DMD) seems to be only partially effective at restoring strength and function to heart muscles.

Boys and young men with DMD and the related Becker muscular dystrophy (BMD) lack the protein dystrophin in their heart and skeletal muscles, leading to progressive weakness and loss of cardiac and respiratory muscle function. Heart-muscle deterioration, or cardiomyopathy, is a leading cause of death in both MDs.

The heart's structural and functional needs for dystrophin may differ from those of skeletal muscles, and a successful therapy must restore function in both types of muscle.

Heart function improved but wasn’t normalized

Researchers at the University of Missouri in Columbia worked with a pared-down working version of the dystrophin gene, or "minidystrophin gene," which codes for the protein missing in DMD and BMD.

This minigene previously has been shown to completely restore skeletal and diaphragm muscle force to normal levels in dystrophin-deficient mice.

However, the minigene only partially normalizes heart function in these mice, the team reported online Dec. 9 in the journal Molecular Therapy.

MDA supported Dongsheng Duan for this work.

The laboratory-made construct, known as the "delta H2-R19 minigene," is modeled after a shortened version of the dystrophin gene associated with extremely mild BMD. To determine whether the construct can reduce heart disease, Duan and colleagues created genetically engineered mice in which this minigene was only active in the heart.

Researchers confirmed distribution of the "mini" dystrophin protein made from the minigene throughout the entire heart and noted that the integrity of the muscle-cell membrane appeared to be restored.

Membrane strength in heart muscle was enhanced, excess formation of connective tissue in the heart muscle was prevented, and the mice performed better on a treadmill test.

However, the minigene expression did not completely normalize heart function, as measured by electrocardiogram (ECG) and cardiac catheterization.

"The hearts of DMD patients throb crazily, much faster than those in healthy people, and dystrophic mice have the same problem," Duan said. "With the minidystrophin protein in the heart, researchers found that the heart began to slow down, but it never reached normal levels."

Also, Duan noted, the major function of the heart is pumping blood, and the diseased heart only pumps out about half of what a normal heart does. "With the help of minidystrophin, more blood was pumped out. However, it only reached approximately 85 percent of normal levels."

Heart muscles may have different dystrophin needs

It's unclear why the minigene that worked so well in skeletal muscle failed to completely normalize heart function.

It may have to do with the specific role of dystrophin in the heart, Duan said. Another possibility, he added, is that the minidystrophin protein is missing important pieces of dystrophin that are necessary for heart function but not essential for skeletal muscle function.

"A full recovery of heart function will require that the therapeutic gene be delivered to and function well in both the heart and skeletal muscle," Duan explained.

"We hope the answer from ongoing studies will lead to a better therapy that will treat both the heart and skeletal muscle disease in patients."

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