SCIENCE / MUSCULAR DYSTROPHY : Researchers See Promise in Gene Therapy

California researchers have developed the first conclusive evidence that a crude form of gene therapy has promise in treating young boys with Duchenne muscular dystrophy.

The controversial new therapy involves a technique called myoblast transfer, in which muscle cells from a donor were injected into a withered leg muscle in the young boys.

Stanford pharmacologist Helen Blau and her colleagues report today in the British journal Nature that the injected cells fused with muscle cells in three of the eight boys treated and began producing the crucial protein that is normally missing in the disorder. She has not yet, however, seen any increase in muscle strength as a result of the treatment.

The defective MD gene was discovered in 1987. It is the blueprint for the previously unknown protein, called dystrophin, whose role in the muscle cell is still not completely understood. But its absence leads to the eventual death of the muscle cells.

Today’s report comes less than a month after similar findings were announced by Tennessee geneticist Peter K. Law of the Cell Therapy Research Foundation in Memphis. Law, in fact, said that myoblast therapy produced pronounced increases in lower body muscle strength in 13 boys he has treated.

But Law’s results have been greeted with skepticism by other researchers who believe that his studies could not rule out alternative causes for the increased strength, especially his use of an immunosuppressive drug called cyclosporine. His initial paper on the increases in strength was submitted to the Lancet, a highly respected journal, which flatly rejected it for not meeting strict scientific criteria.

Furthermore, critics charge that Law’s published report that the missing protein was actually produced in the boys’ muscles after treatment is inconclusive, while Blau’s evidence is, in her own words, “absolutely definitive.” Blau’s results confirm at least part of Law’s controversial results, according to Muscular Dystrophy Assn. President Leon Charash. “It is the largest trial yet to prove that cell transplants can cause dystrophin to be produced in muscle cells,” he said.

But regardless of the controversy over Law’s work, it is becoming clear that myoblast transfer has the potential to become the first effective therapy for Duchenne muscular dystrophy, which kills an average of two boys per day in the United States.

About one in every 3,500 boys born in the United States has the genetic defect that causes Duchenne muscular dystrophy. Females can be carriers of the gene, but rarely develop the disorder.

The affected babies appear normal at birth, but develop a progressive weakening of the muscles that usually places them in a wheelchair by the age of 12. There is currently no therapy for MD and most victims die in their late teens or early 20s when the muscles that operate the heart and lungs cease functioning.

The new therapy is possible because each muscle cell has hundreds to thousands of nuclei, each with its own genetic information. Cells elsewhere in the body have one nucleus. Muscle tissue also contains immature cells, called myoblasts, that can fuse with existing muscle cells and insert their own nuclei.

In their treatment, Blau and her colleagues obtained healthy myoblasts from a biopsy of arm muscles from the father or brother of the MD patients. This tissue sample was grown in the laboratory to produce billions of cells. Finally, millions of myoblasts were inserted into the major muscle of each boy’s leg in 100 injections. As a control, sham injections of saltwater were performed on the opposite leg.

Using a new and highly sensitive test, the Stanford team was able to show that the treated leg in three of the eight boys began producing dystrophin. One boy, who has been studied the longest, has produced it for six months.

Blau is confident that she will be able to obtain much better results as she refines the techniques for administering the cells--confidence based on the demonstration that the treatment works in mice. But she said it will still be several years before such a treatment could be used on a wide basis.