Doctors hail breakthrough in muscular dystrophy treatment

Doctors in the US have raised hopes of a treatment for muscular dystrophy, the most common fatal genetic condition in children, after mending mutations that cause the disease in dogs.

The landmark study is the first to claim success at treating the muscle wasting disorder in large mammals, though scientists on the team caution that more work lies ahead to ensure the procedure is safe and effective for use in people.

If the therapy continues to show promise in future animal studies, researchers believe that a clinical trial involving patients with Duchenne muscular dystrophy could be launched within a few years.

Duchenne muscular dystrophy is caused by mutations that disrupt the normal function of a gene on the X chromosome. The disease mostly affects boys – about one in 3,500 – because they have only one X chromosome. Since girls have two X chromosomes they tend to have a working backup if one copy of the gene is damaged. As a result girls tend not to be affected, but can be carriers and may pass mutated genes on to their children.

The key gene in muscular dystrophy is needed to make dystrophin, a protein which is crucial for strong muscle fibres. If the gene is mutated, the protein cannot be made properly, and muscles throughout the body, including the heart, diaphragm and skeleton steadily weaken and waste away. Most patients die before the age of 30 from breathing or heart problems.

Researchers led by Eric Olson at the University of Texas Southwestern Medical Center used a powerful but experimental gene-editing procedure known as Crispr-Cas9 to correct mutations in the dystrophin gene in four one-month-old dogs. The therapy uses harmless viruses to smuggle the gene-editing molecules into cells. Once inside, they home in on the mutated gene and cut it, causing the cell’s natural repair system to swing into action.

What is Crispr?

Crispr, or to give it its full name, Crispr-Cas9, allows scientists to precisely target and edit pieces of the genome. Crispr is a guide molecule made of RNA, that allows a specific site of interest on the DNA double helix to be targeted. The RNA molecule is attached to Cas9, a bacterial enzyme that works as a pair of “molecular scissors” to cut the DNA at the exact point required. This allows scientists to cut, paste and delete single letters of genetic code.

Working with Olson, Leonela Amoasii injected 20 trillion Crispr-carrying viruses into the lower leg muscles of two young beagles who carried muscular dystrophy mutations. In tests performed six weeks later, the dystrophin levels had been restored to as much as 60% of normal in some muscle fibres. Previous work has suggested that to help patients, dystrophin levels need to boosted to at least 15% of normal levels.

The scientists went on to assess how well the procedure worked if it was delivered by an infusion into the bloodstream instead of directly into muscles. This time, two beagles were infused with either a high or low dose of the Crispr gene editing molecules. Their muscle tissue was examined eight weeks later.

Writing in the journal Science, the researchers describe how the infusions had a variable effect on the dogs’ muscles. In skeletal muscles, dystrophin was boosted by as little as 3% to as much as 90% of normal levels. In crucial diaphragm and heart muscles, dystrophin levels rose to 58% and 92% of normal levels respectively.

“Especially important is the finding that intravenous delivery of the virus resulted in significant restoration of dystrophin in the heart and diaphragm muscles, which are important in this disease,” Olson told the Guardian.

Single Cut CRISPR strategy restores the dystrophin protein. The images illustrate dystrophin (in green) in a healthy diaphragm muscle (left), absence in a canine model of Duchenne muscular dystrophy (center), and restoration of dystrophin in animals treated with CRISPR/Cas9 (right).

Single Cut CRISPR strategy restores the dystrophin protein. The images illustrate dystrophin (in green) in a healthy diaphragm muscle (left), absence in a canine model of Duchenne muscular dystrophy (center), and restoration of dystrophin in animals treated with CRISPR/Cas9 (right). Photograph: Courtesy of UT Southwestern Medical Center/Science

The scientists now plan extensive studies to assess the impact of the treatment on dogs. Those will reveal whether correcting the faulty genes actually improves the animals’ muscles and whether any benefits last. Because the study was small and run over a short time, it is impossible to know how effective the approach might be at alleviating the disease in humans.

“I feel this procedure is extremely promising based on our preliminary findings, but more work is needed to ensure safety and to determine long term durability of dystrophin expression,” Olson said. How soon it can be tested in humans depends on the results of forthcoming long term studies in dogs that will carefully assess the efficacy and safety of the procedure.

“If everything were to continue smoothly, we might be able to anticipate moving into a human trial in a few years, but caution is paramount,” Olson said.

Kate Adcock, director of research and innovation at Muscular Dystrophy UK said it was exciting to see advances in gene editing applied to Duchenne muscular dystrophy, but cautioned that there were limits to the study.

“The sample size was small and the study duration too short to know whether the gene editing was safe and effective,” she said. “Although it seems to have largely boosted dystrophin production, which is key to tackling this condition, the team weren’t looking to record improvements in function. The next step will be to conduct larger, longer-term studies to see if the gene-editing approach does help to slow the progression of the condition and improve muscle strength.

“This won’t be a cure, but that shouldn’t obscure that this is a key step forward in proving the Crispr-Cas9 technology could work for Duchenne.”


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