A boy with X-linked myotubular myopathy. Gene therapy is helping some patients breathe without a ventilator.

Audentes Therapeutics

Boys with a rare muscle disease are breathing on their own, thanks to gene therapy

WASHINGTON, D.C.—A new gene therapy treatment has had striking results in nine boys born with myotubular myopathy (MTM), a rare disease that causes extreme muscle weakness often from birth. All of the boys have better neuromuscular function, most can sit on their own, and four are now breathing without ventilators. As videos of their improvements were shown here on 1 May at the annual meeting of the American Society of Gene & Cell Therapy (ASGCT), the audience broke out in applause. The results, the first of their kind for this rare disease, cap a year of early signs of success in using gene therapy for inherited muscle diseases.

As far as muscle function is concerned, the boys “have gone from nothing to something,” says principal investigator Perry Shieh, a neurologist at the University of California, Los Angeles. “Time will tell how much that something will be.”

The patients in the new study have X-linked MTM, caused by a defect in a gene called MTM1 that encodes an enzyme, myotubularin. Skeletal muscles need the enzyme to develop and function. Boys with the disease have low muscle tone and, in many cases, can barely breathe or move on their own; most require a ventilator and feeding tube. Half of patients die by 18 months, and few live past age 10.

In the trial, sponsored by Audentes Therapeutics, a gene therapy company in San Francisco, California, nine boys between 8 months and 6 years old with X-linked MTM received an intravenous (IV) infusion of many trillions of particles of a harmless virus, called an adeno-associated virus. The viruses were designed to carry a good copy of the MTM1 gene into the boys’ muscle cells. The gene, a free-floating piece of DNA, could then trigger the cell’s proteinmaking machinery to produce myotubularin. Three patients had serious side effects that may have been related to the therapy, such as heart inflammation, but all were treatable.

Biopsies showed that 48 weeks after the first six boys received treatment, their leg muscle cells that previously had virtually no myotubularin were making, on average, 85% of the normal amount, Shieh reported yesterday. The boys’ abnormally small muscle fibers had grown larger. Four can now sit up without help, and three are taking steps with assistance; although still receiving nutrition through a feeding tube, several have started to eat food. And some can vocalize sounds for the first time, Shieh says.

In one set of before-and-after videos, a 1-year-old boy lay passively on an examining table; 48 weeks after his treatment, he could stand and take steps with help. In another, a child who wobbled and needed help to sit up later sat alone and reached out to grab a toy. Three children treated with a higher dose are showing similar motor function gains after 6 months, along with faster changes in their muscle cells and up to double the amount of myotubularin that a healthy child’s cells make, Shieh reported.

“They’re getting great results,” says gene therapy researcher and ASGCT president Michele Calos of Stanford University in Palo Alto, California, who chaired a symposium of the meeting’s top abstracts, where Shieh presented. And in theory, those results could last: Because muscle cells don’t normally divide, the extra myotubularin could keep the boys’ muscles working for years to come. Dogs with a milder form of MTM that received the same therapy and gained the ability to run are still doing fine years later, Shieh notes.

The treatment will be tested in more children before Audentes seeks approval from the U.S. Food and Drug Administration (FDA). Meanwhile, another IV gene therapy, for a rare genetic disease called spinal muscular atrophy that led to dramatic improvements in 15 children is expected to soon become the second FDA-approved gene therapy for an inherited disorder. (The first was gene therapy for an inherited form of blindness in late 2017.)

In the past year, experimental IV gene therapy from the biotech company Sarepta Therapeutics in Cambridge, Massachusetts, has also helped four boys born with Duchenne muscular dystrophy gain muscle strength—they can now more easily climb stairs, for example. And 60 days after a similar treatment, patients with a disease called limb-girdle muscular dystrophy are making substantial amounts of a missing muscle protein, Sarepta recently reported. To see such treatments finally helping patients is “surreal,” says Louise Rodino-Klapac, who spent her career developing these therapies in the lab at Ohio State University and Nationwide Children’s Hospital in Columbus before joining Sarepta last year to head its gene therapy unit.

These and other successes have helped spur an explosion of interest in the field. The ASGCT meeting, which for years attracted about 2000 attendees, drew more than 4800 this year, forcing the hotel hosting the meeting to turn people away from packed rooms and set up tents for some sessions. Many of the new attendees were from biotech companies. That’s a signal, says Calos, that after overcoming early obstacles, gene therapy is now “maturing as a branch of medicine.” From now on, she adds, the meeting will take place at larger venues.