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Gene Therapy

Restoring Dystrophin

A gene therapy technique that many scientists once considered unmanageable has led to a potential “cure” for Duchenne muscular dystrophy (DMD). A Franco-Italian team led by Luis Garcia 1 has for the first time used a technique called “exon skipping” to rehabilitate the protein missing in DMD patients’ stem cells. The modified stem cells improved muscle performance when injected into animal models. 2 “This research could eventually lead to gene therapy that would stop the progress of the disease and restore lost muscle functions,” says Garcia, who coordinated the research with Yvan Torrente from the University of Milan (Italy). Duchenne muscular dystrophy is the most common neuromuscular disease and almost exclusively affects males–nearly one in 3500 boys at birth worldwide. A gene abnormality causes a deficit of dystrophin, a protein that helps stabilize muscle fibers when they are subjected to stress. Since they cannot resist the force exerted on them when they contract, the muscles gradually deteriorate. Although patients seem unaffected at birth, most are in a wheelchair by the age of 10.
Garcia’s team set out to find whether muscle function could be restored in muscles that had already started to deteriorate. They used exon skipping, a type of gene therapy that corrects errors in cellular coding elements known as exons. When it was first proposed in the early 1990s, it was deemed too complicated and far-fetched. But scientists have started to master the technique. In 2004, Garcia’s team showed that it could help restore 90% of the missing dystrophin in mouse models.
In their latest study, researchers used exon skipping to correct the DMD gene mutation in vitro using human stem cells taken from the blood and muscles of DMD patients. They then injected the restored human cells into mouse models. Forty-five days later, the mice were expressing human dystrophin and functional tests showed improved muscle performance.
“At this stage, we can’t be sure that the therapy will have similar effects on humans,” says Garcia. Unlike humans or other animal models, mice suffering from DMD can move almost normally, so it is difficult to evaluate the clinical benefits that could be expected in humans.
The researchers also want to know at what stage of the disease the treatment would be most effective. They believe the best candidates for treatment are boys less than 10 years old who do not show major physical signs of muscle deterioration. “But boys over that age might also benefit,” concludes Garcia.

Anita Elash

Notes :

1. Institut de myologie (CNRS / Inserm / Université Paris-VI).
2. R. Benchaouir et al., “Restoration of Human Dystrophin Following Transplantation of Exon-Skipping-Engineered DMD Patient Stem Cells into Dystrophic Mice,” Cell. Stem Cell, 2007. 1: 646-57.

Contacts :

Luis Garcia,
Institut de myologie, Paris.


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