Gene 'Editing' in Dog Study Shows Promise for Kids With Muscular Dystrophy

For the first time, scientists report using gene-editing technology to halt the progression of muscular dystrophy in dogs -- suggesting a possible breakthrough for children with a form of the disease.

Reporting in the current issue of Science, researchers describe how they used CRISPR technology to edit a naturally occurring genetic flaw that causes a version of Duchenne muscular dystrophy in dogs. CRISPR is an acronym for a family of DNA sequences.

The gene correction, in turn, triggered what the scientists call an "unprecedented" improvement in the animals' muscle fibers.

The discovery might hold the key to helping children with Duchenne MD, the most common form of muscular dystrophy. MD is a group of incurable genetic disorders that cause progressive muscle degeneration.

Duchenne MD primarily affects boys and usually arises in early childhood. Historically, most boys did not survive beyond their teens, but more are living into their 30s these days, according to the Muscular Dystrophy Association.

Duchenne is caused by a mutation in a gene that produces a critical protein called dystrophin. Without it, muscles throughout the body -- including the heart and diaphragm -- break down over time.

"The only real way to correct this disorder is to get the body to produce functional dystrophin," said Eric Olson, lead researcher on the new study. He's professor and director of University of Texas Southwestern Medical Center's Hamon Center for Regenerative Science.

To do that, researchers have been studying gene therapy. But with Duchenne MD, Olson said, there is a hurdle to replacing the defective gene with a functioning one: its size.

"It's simply too massive to replace," he explained.

So Olson and his team took a different approach. They used CRISPR gene-editing technology to fix the gene defect.

The researchers treated four dogs that carried the most common mutation seen in people with Duchenne MD -- affecting a location on the dystrophin gene called exon 51. They used a harmless virus to deliver CRISPR components to the exon -- which the technology then "edited."

Within weeks, the researchers reported, the missing dystrophin protein was restored in muscle throughout the animals' bodies.

The effects were not uniform. In some muscle, dystrophin was produced at 3 percent of its normal level. But in the heart and diaphragm, the protein was restored to 92 percent and 58 percent of normal, respectively.

The researchers also found evidence of improved integrity in the animals' muscle fibers.

Olson put the increases in dystrophin levels in perspective: There is a drug for Duchenne MD -- called Exondys 51, and approved in the United States in 2016 -- that can be used in a minority of patients who have a mutation in exon 51.

It has been shown to restore less than 1 percent of dystrophin in skeletal muscle after one year, Olson pointed out.

"Here, we saw really dramatic changes -- beyond what we'd hoped for," he said.

The findings are "very encouraging," said Dr. Sajel Lala Kana, a clinical geneticist at Nicklaus Children's Hospital in Miami.

But they are also very early, she pointed out. "This study shows what happens in these animals in the short term," said Kana, who was not involved in the research. "But will this be sustainable over a long period of time?"

Olson agreed that that is a critical question. And then there's the issue of whether the gene editing could have unintended adverse effects.

There are two main theoretical safety concerns, according to Olson: "Are there any off-target effects?" he said. "That is, could this accidentally affect the expression of other genes?"

Another question, Olson said, is whether the immune system will react to the enzyme CRISPR uses to make its gene fixes. So far, there have been no signs of that, the researchers said.

While animal studies frequently don't produce the same results in humans, Olson said these findings can be seen as a promising early step.

"We're working hard on trying to treat the cause of this disease," he said. "With further study in animals, in a few years we may be able to move into human trials."

Kana agreed. "There's a lot of research going on this field," she said. "This is how we'll move toward a cure someday."

In the United States, Duchenne MD affects one in every 3,500 to 6,000 boys born each year, according to the National Institutes of Health. Often, the agency says, there is no family history of the disease; instead, mutations spontaneously occur in the dystrophin gene.

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