Muscular Dystrophy Advance Reported : Medicine: Implants of healthy cells in a boy’s diseased toe appear to trigger production of a vital protein. Researchers stress preliminary nature of findings.
Healthy muscle cells implanted into the toe of a 10-year-old boy with Duchenne muscular dystrophy have apparently reversed the effects of the degenerative disease in the boy’s toe muscles, a Tennessee researcher reported Saturday.
The achievement apparently marks the first time that a genetic defect has been corrected in humans--albeit on a very small scale.
The injected cells caused the toe muscles to begin producing a protein that is normally missing in Duchenne muscular dystrophy, for which there has been no effective therapy. Neurologist Peter J. Law of the University of Tennessee at Memphis told a meeting of the Muscular Dystrophy Assn. in Tucson that “very preliminary” results indicate there is some improvement in function of the toe as well.
Law is so encouraged by the results, he said in a telephone interview, that later this year he hopes to inject more cells into the legs of three boys whose toes have been treated.
“This is very exciting and very hopeful,” said Dr. Lawrence Stern, medical director of the Muscular Dystrophy Assn. “One of the most significant things we can say is that this is a potential treatment for all degenerative muscular diseases.”
But the researchers are cautious in their assessment because results have been reported for only one patient. “Many more questions must be answered and much remains to be done before the procedure can become a (routine) treatment,” said Dr. Leon I. Charash, chairman of the association’s medical advisory committee, “but Dr. Law’s finding is an exciting first sign of success.”
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 defective gene, but they rarely contract the disorder themselves.
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 11. Most die in their late teens or early 20s, when the muscles that operate the heart and lungs cease functioning.
A major breakthrough occurred in December, 1987, when pediatrician Louis J. Kunkel and his colleagues at the Harvard Medical School reported that they had isolated the gene that is defective in the disease. The gene is the blueprint for a protein they called dystrophin.
Dystrophin makes up part of the structure of the muscle cells, but is present in only tiny quantities even in healthy cells, accounting for only 0.002% of the protein in muscle cells. In Duchenne muscular dystrophy victims, virtually no dystrophin is produced.
The new therapy is possible because each muscle cell, unlike every other cell in the body, has hundreds to thousands of nuclei, each with its own--but identical--genetic information. Muscle tissue also contains immature cells, called myoblasts, that can fuse with existing muscle cells, insert their own nuclei, and cause the muscles to regenerate.
Last year, three different groups of researchers independently found that healthy myoblasts injected into the muscles of mice with muscular dystrophy-like diseases would fuse with the defective cells and begin producing dystrophin. Two of the groups worked with the most common mouse model of the disease, in which the muscular cells do not degenerate, so they could not assess functional improvement. The fact that the cells began producing dystrophin, however, suggested that the treatment could be an effective therapy.
Law, however, worked with a different mouse model in which muscles do degenerate and the mice die by the age of nine months. He found that the muscles in the mice that received myoblast injections did not degenerate as rapidly, and that many of the animals lived at least 19 months. Spurred by these results, many physicians began planning human trials.
In February, Law injected about 8 million healthy myoblasts into a large muscle in the toe of 10-year-old Sam Looper of Pickens, S.C. Those cells, donated by Sam’s father Larry, fused with Sam’s toe muscle cells, which began producing the protein that is missing in muscular dystrophy.
Law has treated seven other boys in the same manner, but they have not been studied as long, and three others are awaiting treatment.
Neurologist George Karpati of the Montreal Neurological Institute in Toronto, began similar trials in April, but has not reported any results. Other studies are scheduled to begin later this year at Children’s Hospital in San Francisco and the New England Medical Center in Boston.
All of the researchers are focusing initially on small, relatively unimportant muscles, such as the extensor digitorium brevis in Sam Looper’s toe. Law is able to compare the injected muscle in the right toe to its uninjected counterpart in the left toe to determine if the transplant is effective.
But perhaps more important, the muscles used in all cases are not crucial to the patients’ functioning, so the patients will not be harmed if the experiments go awry and the muscles are inadvertently damaged. The fact that Sam was not harmed by either the injections or by the immunosuppression used to prevent rejection of the injected cells is crucial, said Stern. “That may be the most significant finding” because it means that further experiments can be conducted safely, he said.
Law has already collected the cells necessary for injection into the legs of Sam and two other boys. In two cases, the cells were donated by fathers and in the third by a brother. He plans to apply immediately to the university’s institutional review board for approval of the trials and expects to receive approval sometime this year.
“We hope to move on very fast,” he said.
