Gene-editing technique offers hope to treat muscle disorder: studies

Scientists have used a new gene-editing technique called CRISPR to treat an adult mouse model of Duchenne muscular dystrophy, marking the first time that such a tool has successfully treated a genetic disease inside a living mammal.

Duchenne muscular dystrophy is caused by problems with the body's ability to produce dystrophin, a long protein chain that is coded by a gene containing 79 protein-coding regions known as exons. If any one of the exons gets a debilitating mutation, the chain does not get built. Without dystrophin, muscle tends to shred and slowly deteriorate.

The disease affects one in 3,500 to 5,000 boys, according to the U.S. Centers for Disease Control and Prevention and other estimates, and often leads to premature death by the early 30s.

Now, three independent studies, published in the Friday issue of U.S. journal Science, showed that the recently developed gene-editing technique has the potential to treat those who suffer from Duchenne muscular dystrophy.

In the first study, researchers from the Duke University worked with a mouse model that has a debilitating mutation on one of the exons of the dystrophin gene.

They programmed the CRISPR system to snip out the dysfunctional exon, leaving the body's natural repair system to stitch the remaining gene back together to create a shortened -- but functional -- version of the gene.

With the help of a non-pathogenic carrier called adeno-associated virus 8 (AAV8), the team first delivered the therapy directly to a leg muscle in an adult mouse, resulting in the restoration of functional dystrophin and an increase in muscle strength.

They then injected the CRISPR/AAV8 combination into a mouse's bloodstream to reach every muscle and found some correction of muscles throughout the body, including in the heart -- a major victory because heart failure is often the cause of death for Duchenne patients.

"There is still a significant amount of work to do to translate this to a human therapy and demonstrate safety," said lead author Charles Gersbach, associate professor of biomedical engineering at the Duke University. "But these results coming from our first experiments are very exciting."

In a second study, Chengzu Long and colleagues from the University of Texas used adeno-associated virus-9 (AAV9), which displays a high affinity for muscle, to deliver the CRISPR editing components into the abdomen, into muscles, or into the backs of eyes of newly born mice.

While each delivery method had its unique benefits and improved muscle function, they found that dystrophin protein levels were highest when the treatment was injected directly into muscles.

A third study by scientists at the Harvard University also used CRISPR and AAV9 to edit out one of the dysfunctional exons of the dystrophin gene, finding similar beneficial restoration of muscle functioning.

"Recent discussion about using CRISPR to correct genetic mutations in human embryos has rightfully generated considerable concern regarding the ethical implications of such an approach," said Gersbach.

"But using CRISPR to correct genetic mutations in the affected tissues of sick patients is not under debate. These studies show a path where that's possible, but there's still a considerable amount of work to do," he said. Endit