Researchers Remove Gene Defect in Common Form of Muscular Dystrophy

Muscular Dystrophy Association
Sunday, 6 July 2003

A laboratory-engineered compound that snips out a defect in the gene for the muscle protein dystrophin has been successfully used to treat a disease resembling Duchenne muscular dystrophy in mice, the Muscular Dystrophy Association announced today.

Duchenne muscular dystrophy, the most common childhood MD, results from a defect (mutation) in the dystrophin gene, which normally carries instructions for an important muscle protein.

MDA grantee Stephen Wilton, a molecular biologist at the Centre for Neuromuscular and Neurological Disorders of the University of Western Australia in Perth, was on the research team, which published its findings in the August issue of Nature Medicine. (The paper is posted at www.nature.com/nm.)

Terry Partridge, an investigator with the Muscle Cell Biology Group at the Imperial College of Medicine in London, was also part of the study. Partridge has received MDA funding for related muscle biology work.

"We're very enthusiastic about this approach, because in this research group's hands, it's relatively efficient," MDA's Director of Research Development Sharon Hesterlee said. "It also seems to get around some of the potential problems we've seen with other methods, such as rejection by the immune system when viruses are used to deliver corrected genes.

"We'll be aggressively working with this group to design follow-up studies to put us on the path toward human trials."

Duchenne muscular dystrophy is a progressive, muscle-wasting disease that affects boys almost exclusively and weakens voluntary muscles, as well as the muscles of the heart and respiratory system. Boys with the disease deteriorate throughout childhood and adolescence and usually die in early adulthood.

The current study, conducted in Australia, England and Wales, takes a new approach to treating Duchenne by snipping out, in dystrophin-deficient mice, the part of the dystrophin genetic instructions that contain an error (mutation). The mutation in these animals is a "stop sign" that causes the cell to stop processing the instructions before they've been completely "read" and interpreted by the cell, leading to production of a very short and nonfunctional dystrophin protein.

Wilton and his group caused the mouse muscle cells to ignore the stop sign and translate the genetic instructions, minus those containing the "stop sign" error, into near-normal dystrophin protein molecules. Their method used a compound containing "an antisense oligo," a molecule that attaches to the dystrophin genetic instructions near the mutation and keeps the stop sign from being noticed by the cell; and a molecule called F127, which improves antisense delivery to muscle cells.

The mice received injections of the antisense-F127 combination into a leg muscle. Two to four weeks later, the injected muscles contained what the investigators believe is a nearly normal amount of dystrophin in about 20 percent of their muscle fibers.

The scientists also found the treated muscles could produce more force than untreated, dystrophin-deficient muscles but weren't as strong as normal mouse muscles.

The mice accepted the newly produced dystrophin without mounting an immune-system attack, even when a second injection was given.

"Although very exciting, there is still a long way to go," Wilton said. "We're currently looking at ways to make the drug more stable and biologically active. It must be shown, for instance, that the antisense-F127 compound can be used safely over a long period, because this will be a treatment, not a permanent cure. We have to determine how long the beneficial effects last and establish appropriate treatment regimens."

Partridge, who was at first skeptical of the error-skipping strategy, said, "I myself am a convert to this idea, but the main hurdle is to see whether it can be made to work on a whole-body scale. If it can, then human trials could be contemplated."

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. The Association's programs are funded almost entirely by individual private contributors.

For more information, or to contact Muscular Dystrophy Association, see their website at: www.mdausa.org