Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders in boys. Mutations in the dystrophin (DMD) gene cause progressive muscle wasting and lead to paralysis and death. Researchers have long hoped to restore dystrophin function by inserting a working copy of the gene into muscle cells. But at more than 2.5 million base pairs, it is one of the longest genes in the human genome and one of the most difficult to manipulate.

In the December issue of Cell Stem Cell1, researchers led by Yvan Torrent, from the University of Milan, and Luis Garcia, at the French National Institute of Health and Medical Research (INSERM), report that a genetic patch can repair the defective dystrophin gene in adult human stem cells. Moreover, when mice with DMD are injected with these cells, their muscles grow and function better. The findings suggest that one day doctors may be able to treat the disease using a patient's own cells, reducing the possibility of rejection.

Dystrophin gene mutations generate a transcript that cannot be translated into a protein. In the Cell Stem Cell paper, the researchers used antisense oligonucleotides to mask the mutations responsible for the defective transcript. (More specifically, they used antisense RNA sequences that caused the cellular machinery to skip problematic exons within the gene.) Although the resulting transcript differs from the normal gene variant, it can still produce a functional protein.

The researchers collected adult muscle stem cells from boys with DMD, modified those cells with their genetic patch, and injected them into the arteries and muscles of dystrophic mice. The transplanted stem cells produced functional human dystrophin.

The group is currently testing this approach in dogs, which are subject to a condition that more closely resembles human DMD, to see if the therapy improves their gait, but clinical trials are still a ways off.

Caution is warranted. Last year a study by other researchers found that dogs with muscular dystrophy could be helped by injections of a type of stem cell called a mesoangioblast, scraped from the blood vessels of normal dogs. Injecting genetically corrected cells from the diseased dogs had little effect, possibly because the researchers used a shorter version of the gene that was easier to work with2. A recent Brief Communication in Nature questioned how well the treatments using cells from normal dogs worked3.

Still, a dual approach of using both cell and gene-based therapies has several advantages, says Garcia. “It brings new cells into a system that needs new progenitors...and there is no rejection of the cells because they belong to the patient.”

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