A gene therapy advance for muscle-wasting myotubular myopathy

X-linked myotubular myopathy XLMTM gene therapy
Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study. (Read more of her story.)

For more than two decades, Alan Beggs, PhD, at Boston Children’s Hospital has explored the genetic causes of congenital myopathies, disorders that weaken children’s muscles, and investigated how the mutations lead to muscle weakness. For one life-threatening disorder, X-linked myotubular myopathy (XLMTM), the work is approaching potential payoff, in the form of a clinical gene therapy trial.

Boys with XLMTM are born so weak that they are dependent on ventilators and feeding tubes to survive. Almost half die before 18 months of age.

In 1996, a French group cloned the affected gene, MTM1. In 2013, Beggs and Anna Buj-Bello, PhD, at Généthon showed that replacing the missing protein in mice improves weakened muscles’ ability to contract. The next year, a gene therapy study led by Beggs, Buj-Bello and Martin Childers, DO, PhD, at the University of Washington showed promising increases in muscle strength in a colony of Labrador retrievers who harbored the same mutation.

And a study published earlier this month in Molecular Therapy provides more validation, showing that 10-week-old Labrador retrievers, already showing signs of the disease, looked and acted like normal dogs a year after a single systemic injection of the gene therapy vector.

The Labs showed improvements in breathing, limb strength and walking gait that increased with the dose given. On biopsy, their muscle pathology was almost completely reversed. There were no apparent adverse effects, even at the highest doses.

X-linked myotubular myopathy XLMTM gene therapy
Courtesy Martin Childers Lab

“We report here a gene therapy dose-finding study in a large animal model of a severe muscle disease where a single treatment resulted in dramatic rescue,” said Childers in a press release.

“This represents an important finding: that treating dogs late in their disease course still works,” says Beggs, a coauthor on the paper. “This is important because that is the situation most human patients will be in.”

Beggs continues to be involved in the research, including a follow-up study in the dogs to determine how long-lasting the treatment benefits are. He is also leading a natural history study of X-linked myotubular myopathy, designed to further understand the disease and lay the groundwork for future clinical trials (assuming safety studies pan out). Clinical development is being led by Audentes Therapeutics under the name AT132; Beggs is on the company’s board of scientific and clinical advisors.

Read more background and the story of Nibs, the XLMTM carrier dog whose descendants took part in the study.