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Doctors Plan Bold Test of Gene Therapy on Boys with Muscular Dystrophy

How an unusual medical case in the 1990s provided a clue for how to treat a fatal muscle disease.
Image courtesy of Chady Hakim/ Duan Lab, University of Missouri

In 1990, a British muscular dystrophy researcher, Kay Davies, described the unusual case of a 61-year-old man who by rights should not have been alive, given what was known of the disease at that time.

The muscle wasting disease is caused by mutations to the dystrophin gene. Even just one wrong genetic letter can mean early death. Remarkably, the man Davies described was missing 46 percent of the gene. Yet there he was, still walking with the aid of a stick in his seventh decade.

Now that 27-year-old discovery is leading to what could be the best chance to treat—and maybe stop—a serious form of the disease, Duchenne muscular dystrophy.

Using mini-genes inspired by the man’s genetic defect, three U.S. teams say they are ready to try to treat Duchenne with gene therapy. The first study could begin as soon as next month at Nationwide Children’s Hospital in Columbus, Ohio, with the backing of a biotech firm, Sarepta Therapeutics, and a charity, Parent Project Muscular Dystrophy.

Two other tests on children, one organized by Solid Biosciences, of Cambridge, Massachusetts, and the other by drug giant Pfizer, are slated to begin by year’s end and in the first half of 2018, respectively.  

Each will test a “microdystrophin,” meaning a foreshortened copy of the dystrophin gene that’s small enough to fit inside a virus, which is required to shuttle the genetic information into a person’s cells. The immense size of the gene is what’s prevented attempts at gene replacement until now.

Duchenne muscular dystrophy strikes one in every few thousand boys, but rarely affects girls. By their teens, most boys can’t walk anymore. They often die in their 20s and there are few treatment options.

Although the mini-genes won’t be perfect, doctors hope that boys who receive them will end up with a mild handicap—much the like man Davies described had—instead of a death sentence. Already, the Nationwide and other studies have waiting lists, even before being formally announced.  

“You can imagine a dramatic effect. We could extend the life of [these] kids by years or decades,” says Scott Harper, an associate professor of pediatrics at Ohio State University who works with the Columbus gene-therapy center, but isn't involved in the new clinical trial.

Gene therapy, in which a replacement gene is delivered to a person’s cells, is offering radical new hopes for some conditions. Diseases being treated, or simply cured, include hemophilia and immune disorders.

But the sheer size of the dystrophin gene has been an obstacle for Duchenne. It manufactures a spring-like protein involved in guarding muscles. Clocking in at around 14,000 letters, it is the third-largest gene in the human body, according to Cold Spring Harbor biologist Jason Sheltzer.

That is more than three times larger than what can fit inside a virus of the type used to deliver genes to muscles.

What Davies and others realized is that nature had serendipitously pointed out a solution in the genome of that 61-year-old. Maybe the gene could be made shorter and still function. By 2002, Harper and a scientist named Jeff Chamberlain had cut down the gene by removing enough unnecessary parts so it had only about 4,000 letters.

“It was rational design based on known biology of a patient,” says Harper, who carried out the project as a graduate student.

That original microdystrophin design is similar to the one that’s going to be tested in boys at Nationwide. Yet attempts to treat anyone with it had to wait a further 15 years as gene-therapy technology developed. Finding a virus able to deliver its payloads to the heart, diaphragm, and limb muscles proved difficult. And manufacturing them in the large volumes needed for trials remains tricky to this day.

Pat Furlong, founder of the charity supporting the Columbus study, says her group is supplying $2.4 million to Nationwide to help finance the first-of-a-kind effort. Most of the expense, she says, is for producing the viral particles, which are grown in high-tech clean rooms.

Scientists also needed to first demonstrate that their idea worked in animals roughly the same size as children. Those experiments, carried out by several other gene-therapy centers using Golden retrievers with a form of muscular dystrophy, have been promising.

This month, for instance, the French gene-therapy center Genethon released videos of dogs treated with a different mini-gene jumping over a low plastic gate to reach a toy. Dogs that didn’t get the gene therapy turned circles but couldn’t reach it.

Some other biotechnology companies, including Exonics and Editas Medicine, think the gene-editing technology called CRISPR could be a better approach. Instead of adding a gene, they hope to use gene editing to restore dystrophin to its nearly complete form by tweaking away spelling errors.

Eric Olson, a researcher at UT Southwestern and a founder of Exonics, calls early CRISPR results in large animals “mind blowing.” But CRISPR is new enough that there’s no time line for the first gene-editing trials in boys. That could still be years away.

Parents instead are clamoring to get their boys into the trial at Nationwide as well as one being planned by Solid Biosciences, which says it hopes to have clearance to begin this year. “People are calling, ‘Can you get my boy in?’” says Furlong. She doesn’t have any sway over who is chosen, but says the possibility of a cure is “a subject of open discussion at conferences and in corridors.”

According to Furlong, the microdystrophin trial at Nationwide envisages treating a small number of boys, divided into two groups. One will be infants three months to three years of age; the other consists of older kids, up to seven years old. They will each have quadrillions of the viruses released into their blood through a single IV drip.

Louise Rodino-Klapac, who is a principal investigator of the study and also a pediatrics professor at Ohio State University, said approximately 12 children will be treated. She did not confirm the age groups, noting that details of the trial have not been formally released. She also said there are still some possible ways the study could fail. “The risks include whether patients already have too much damage [and] whether the synthetic gene causes an immune reaction in some patients, causing the body to eliminate it,” she says.

Rodino-Klapac, who leads the study along with gene-therapy specialist Jerry Mendell, says it will be the first time doctors have tried to reach every muscle in the body with a microgene therapy in an attempt to achieve a “therapeutic effect.” 

All that creates high stakes. The earlier a boy is treated, doctors believe, the more muscle cells he’ll still have left and the greater the chance of success. And given the slow pace of drug development—and of gene therapy in particular—some parents see the new microgene trials as their best, and maybe only, chance before their boys are off their feet, in wheelchairs, and no longer eligible.

“It’s a very big decision to say to yourself, ‘Will I do gene therapy?’” says Rodino-Klapac. Based on all the evidence so far, she says: “If you have a young child, there is reason to be optimistic.”

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