Study Points to Lithium as Potential Treatment for Limb Girdle Muscular Dystrophy

Rare Daily Staff

A team at Washington University School of Medicine in St. Louis discovered that lithium improves muscle size and strength in mice with a form of limb girdle muscular dystrophy, a rare and progressive muscle wasting disease.

The study, published April 18 in Neurology Genetics, could lead to a drug for the disabling condition.

Limb girdle muscular dystrophy can be caused by variations in any one of more than a dozen different genes. It causes progressive weakness in the shoulders and hips. Over time, people with the condition lose the ability to walk or to lift their arms above their heads.

“There are no medications available for people with limb girdle muscular dystrophy, so we are very excited to have a good therapeutic target and a potential therapy,” said senior author C. Chris Weihl, a professor of neurology who treats people with muscular dystrophy at the Washington University’s Neuromuscular Disease Center. “Genetic sequencing then helped us identify a new subtype, and we’ve been able to take that all the way through to a possible therapy.”

The work began when Weihl and his colleagues identified two families in which several members had symptoms of the condition but none of the known genetic variants. By analyzing the DNA of affected and unaffected members of both families, the researchers found that a variation in the gene DNAJB6 was responsible for their muscle weakness.

Although the researchers identified the faulty gene, it wasn’t clear why an alteration to that gene caused people’s muscles to atrophy. To find out, researchers cut the gene out entirely, expecting to see even more muscle loss when the gene was absent. What they found, though, was that when the gene was eliminated, muscle fibers grew to three times their normal size.

The researchers then used genetically modified mice they had engineered with the same genetic variant as the patients. Like the patients, they developed progressive muscle weakness in adulthood. Using muscle from these mice, the researchers discovered that disease variants over-activate a protein that suppresses muscle growth. Moreover, inhibiting the protein—called GSK3beta—with lithium chloride improves mice’s strength and muscle mass.

The mice had one-fifth the strength of the normal mice. But after a month of treatment, the researchers said they improved to 75 percent of the normal mice.

Lithium chloride was once sold as table salt but was removed from the market because of safety concerns. Other forms of lithium are used to treat some psychiatric illnesses. The researchers believe it’s possible a safe form of lithium can be found to treat the rare muscular dystrophy.

Before any compound targeting the protein is tested in humans, a better understanding of limb girdle muscular dystrophy is needed.

Weihl and his colleagues in the United States and United Kingdom are planning a study of people with limb girdle muscular dystrophy caused by variations in any gene. The study will map disease progression in preparation for upcoming treatment trials. Participants will make annual visits to the neuromuscular clinic to undergo functional assessments and fill out questionnaires rating their ability to perform tasks of daily life.

“We’re at a point where therapeutic development has outpaced our understanding of the natural history of this disease,” Weihl said. “We have a therapeutic target, but we don’t fully understand how patients progress when they’re not treated. We need to understand as many people with this rare disease as possible so when we do start testing an investigational drug, we can be confident that it is changing the course of the disease.”

Photo: C. Chris Weihl, professor of neurology, Washington University School of Medicine in St. Louis