Discovery Could Lead to Muscular Dystrophy Therapy : Health: Researchers report finding the mechanism by which muscle cells are destroyed in

Berkeley researchers for the first time have determined the mechanism by which muscle cells are destroyed in Duchenne muscular dystrophy, a discovery that could lead to the development of new forms of drug therapy for the disorder.

UC Berkeley biologist Richard Steinhardt and his colleagues report today in Science magazine that the destruction in both mouse and human cells is caused by a defect in cellular membranes that allows destructively high levels of calcium atoms to enter muscle cells and cause them to degenerate.

In light of this finding, researchers at UC San Francisco and elsewhere are already planning clinical trials of drugs that might block entry of calcium into muscle cells in hopes that the drugs will prevent muscle degeneration.

A family of drugs called calcium blockers is already used to treat heart disease and high blood pressure, and researchers hope that one of these or a similar drug might prove to be an effective therapy for muscular dystrophy as well.

“We’re giving drug manufacturers a target for the development of new drugs for attacking muscular dystrophy, as well as a way to (measure) the effectiveness of a new drug,” Steinhardt said.

The new findings complement the recent discovery of the defective gene for Duchenne muscular dystrophy and provide insight into how the defective protein produced by the gene may damage muscle cells.

Researchers have been attempting to replace the defective gene in the muscle cells of muscular dystrophy victims using a technique called myoblast transfer therapy, and today’s new finding may provide an “exciting” alternate way to attack the devastating disease, according to Lawrence Stern, president of the Muscular Dystrophy Assn.

Babies with muscular dystrophy appear normal at birth but develop a progressive weakening of the muscles that usually places them in a wheelchair by the age of 11. There is no effective therapy for the disease, and most victims die in their late teens or early 20s when the muscles that operate the heart and lungs cease functioning.

Researchers found the gene that causes Duchenne muscular dystrophy three years ago. The healthy gene is the blueprint for a protein, called dystrophin, that allows muscle cells to function properly. “Now the question is how does the lack of dystrophin result in this fatal disease?” Stern said. “That’s where the large research thrust is.”

The Berkeley results indicate that dystrophin is somehow involved in regulation of the entry of charged calcium atoms into muscle cells through so-called calcium channels.

These calcium ions are required for normal function of the muscle cells, but the defective dystrophin allows much higher levels of calcium to enter the cells, Steinhardt found. Those increased levels stimulate the activity of enzymes called proteases that break down proteins within the muscle cells.

“The muscles are literally digesting themselves,” Steinhardt said.

Stern noted that similar calcium channels are present in heart and blood vessel tissues, but that they had never been found before in muscle cells. The channels’ involvement in causing muscular dystrophy, he added, “gives us a theoretical and, perhaps soon, practical approach to a treatment. We need to find a drug that blocks this abnormal channel, and there are certain types of drugs that seem to be suited to this type of job.”

Steinhardt said he has not yet found any drugs that block the channel and prevent calcium from entering the cell. But UCSF neurophysiologist Jeffrey B. Lansman said he has tentatively identified at least one such drug, which he will not yet name, and that he and other researchers are planning clinical trials of it as soon as their research protocol is approved by their institutional bioethics review panels.

“We want to give it in very small doses to patients that have already been observed for a long time so that we can see whether it will slow the progression of the disease,” he said.

Meanwhile, researchers elsewhere have been studying myoblast transfer as a potential therapy for muscular dystrophy. In this approach, healthy embryonic muscle cells from a relative are injected into the patient’s muscle tissues. The genes in the healthy cells are inserted into the defective cells and stimulate the production of dystrophin.

Neurologist Peter J. Law of the University of Tennessee reported earlier this week at a meeting of the Society for Neuroscience that injection of such cells into the big toes of three muscular dystrophy patients led to as much as an 80% increase in functioning of the muscles. Researchers now plan to try the technique on muscles that would be more useful to the patient, such as arm and finger muscles.

Stern said that both myoblast transfer and the use of drugs look very promising, and that the two approaches could prove complementary. “We’re going to support every approach that could lead to a treatment to the hilt.”