Combined therapy could repair and prevent damage in Duchenne muscular dystrophy

Public release date: 9-Aug-2013 [ | E-mail | Share ]

Contact: Gina Bericchia Gina.Bericchia@NationwideChildrens.org 614-355-0495 Nationwide Children's Hospital

New research on two promising gene therapies suggests that combining them into one treatment not only repairs muscle damage caused by Duchenne muscular dystrophy, but also prevents future injury from the muscle-wasting disease. The work, led by a team at The Research Institute at Nationwide Children's Hospital, is the first to look at the approach in aged mice, a key step toward clinical trials in patients. The findings were published in July in Human Molecular Genetics.

"We're excited about the fact that these are older mice and we're still able to see a sustained functional benefit from this combined therapythis hasn't been shown before," says Louise Rodino-Klapac, PhD, a principle investigator in the Center for Gene Therapy at Nationwide Children's and lead author of the research.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in children, affecting about one out of every 3,500 to 6,000 male births. Symptoms usually begin between the ages of 3 and 5 years and progress rapidly. Most patients are unable to walk by age 12 and ultimately need a respirator to breathe.

Patients with DMD lack the gene that makes dystrophin, a protein vital for healthy muscle tissue. Dystrophin acts as an anchor to support muscle fiber strength and prevent injury. Without it over time, the muscle degenerates, scar tissue builds up and fat slowly replaces the dead muscle. The gene that produces dystrophin is hugethe largest known gene in the bodyso a much smaller version, called micro-dystrophin, has been developed for gene replacement therapeutic studies.

Another gene replacement therapy currently under study in patients with different forms of muscular dystrophy is follistatin 344, which produces a protein that enhances muscle strength and prevents atrophy.

While preliminary studies in animals of each of these therapies suggest they offer some benefit when used individually, the team at Nationwide Children's wanted to see what would happen if the therapies were combined.

Dr. Rodino-Klapac and her colleagues packaged the micro-dystrophin and follistatin therapeutic genes into adeno-associated virus, which doesn't cause disease and isn't absorbed in the genome. The virus and its genetic cargo were delivered via injection to dystrophic mice that were either 6 or 12 months old. The virus "infects" cells, the therapeutic genes are released, and the body ideally begins to produce micro-dystrophinwhich prevents future muscle injuriesand follistatinwhich repairs existing muscle damage.

The researchers analyzed skeletal muscle strength in the mice at 12 and 20 months of age. Mice that received the combined therapy showed a significant increase in muscle strength compared to mice treated with either the micro-dystrophin or follistatin 344 alone. Equally important, the treated mice also suffered less muscle damage over time.

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Combined therapy could repair and prevent damage in Duchenne muscular dystrophy