New tools for muscular dystrophy research.

Years of telethons; have painted an indelible image of the debilitating effects of muscular dystrophy. The most common form, Duchenne muscular dystrophy, strikes about 1 in 3,500 boys, first wasting their muscles and then killing them in early adulthood. These youngsters lack dystrophin, a muscle protein that acts as scaffolding for muscle fibers.

The identification of dystrophin in 1987 led quickly to the idea of treating the disease by injecting dystrophin-producing cells into diseased muscles. But that strategy hasn't worked. Muscle cells grown from tissue samples taken from healthy parents of muscular dystrophy patients haven't helped the patients' musculature.

The dystrophin-rich muscle cells seem to vanish, although they are not usually attacked by the recipient's immune system. "You inject a million cells, and 95 percent are gone in the first day," says Louis M. Kunkel of the Howard Hughes Medical Institute at Children's Hospital in Boston. Now, however, he and his collaborators have learned that the remaining injected cells were still in place up to 6 months later. What's more, their genes hadn't been silenced. Some of the cells were producing dystrophin, reviving hope for the cell-transplant approach.

The researchers used a technique that combined traditional tissue analysis with a complex series of chemical treatments to reanalyze muscle tissue taken from six muscular dystrophy patients 1 month and 6 months after they had been injected with muscle cells from a healthy parent.

The new technique, developed by Emanuela Gussoni of Children's Hospital, located up to 14 times as many transplanted cells as had been previously detected in this same tissue. Of the cells injected, 5 percent had survived and half of those were producing dystrophin. The patients, however, hadn't regained use of the muscles.

Before Gussoni devised the method, "we didn't have a way of following donor nuclei at the cell level," says study coauthor Helen M. Blau, a molecular pharmacologist at Stanford University School of Medicine. The findings appear in the September Nature Medicine.

The greatest number of donor cells persisted in the healthiest tissue, suggesting that younger patients might benefit most from such cell transplantation, Blau says.

Kunkel believes that better purification of the donor cells may enable more to survive in the patient. Studies in mice lacking the dystrophin gene have shown that to keep the muscle from degenerating, cell injections must result in 10 percent of the donor cells producing dystrophin. "The assumption is, that's true for humans, too," Kunkel says.

Meanwhile, two teams of researchers--at Washington University School of Medicine in St. Louis and at the University of Oxford in England--report in the Aug. 22 Cell that for the first time they have bred mice with the symptoms of Duchenne muscular dystrophy. Previous attempts to use mice as models for the disease had left researchers baffled because a lack of dystrophin didn't seem to hinder the rodents. Unlike humans, they appear to compensate with a related protein, utrophin.

Both groups have now produced mice that lack genes encoding dystrophin and utrophin, explains R. Mark Grady of Washington University, creating a model for scientists to study. "You can use them to try therapies that you wouldn't want to try out on children," such as gene therapy and strong drugs.