Mark McDonald has Duchenne muscular dystrophy, the most common lethal genetic disease diagnosed in children. His father Robert McDonald, MD '88, finds hope in MU's gene therapy research, which has received a new $2.1 million grant from the National Institutes of Health.

Getting to the Heart of Muscular Dystrophy

Gene therapy researcher awarded NIH grant
to protect cardiac muscles from deadly disease

Children with Duchenne muscular dystrophy (DMD) face a future of rapidly weakening muscles, which usually leads to death by respiratory or cardiac failure before their 30th birthday. While researchers are hopeful that gene therapy could eventually evolve into an effective treatment, few have targeted the heart of the problem as much as Dongsheng Duan, PhD.

Duan hopes a new $2.1 million grant he received from the National Institutes of Health will help him develop a treatment that prevents heart muscles from weakening as a result of DMD. As many as 40 percent of patients with the inherited disorder die from heart failure because their weakened cardiac muscles can't pump enough blood to sustain life.

Children with DMD, which is often seen in boys, experience weakening of both skeletal muscle and heart muscle due to a defective gene for dystrophin, a type of muscle protein. Researchers have developed a synthetic dystrophin gene that has shown to be effective in treating skeletal muscle, but Duan's findings published in the journal Molecular Therapy show that cardiac muscle requires different treatment. In fact, tests in an animal model have shown that treating skeletal muscle alone while leaving cardiac muscle untreated can lead to serious complications: Stronger skeletal muscles mean patients can be more physically active, which requires a stronger heart to pump blood throughout the body.

"We've demonstrated that the gene therapy that works for the skeletal muscle doesn't necessarily work for the heart," Duan said. "If we want a more comprehensive treatment, we cannot ignore how the disease affects cardiac muscle."

Duan's lab has analyzed data on thousands of patients with DMD to identify common patterns in deletions on the dystrophin gene that could have led to heart-specific muscle weakness. Now the researcher is developing a new synthetic gene that he hopes will comprehensively treat muscles weakened by DMD.

"We're developing this gene based on what we already know about skeletal muscle, so it will not only be perfectly functional for skeletal muscle but also therapeutic for heart muscle," said Duan, a Margaret Proctor Mulligan Distinguished Professor in Medical Research in MU's Department of Molecular Microbiology and Immunology.

Duan plans to evaluate the newly developed gene in dystrophic mouse and dog models. With funding from additional NIH grants, Duan's team is developing viral vectors for carrying the most important parts of the therapeutic genes to diseased muscle cells. The therapy-carrying viruses will be injected directly into the blood system or the muscles. Following therapy, researchers will perform a series of tests to evaluate the strength of the heart muscle and the effect of the treatment.

"Researchers are more advanced in their understanding of Duchenne muscular dystrophy when it comes to skeletal muscle, but cardiac and skeletal muscle need to be simultaneously treated in patients," Duan said. "This is just the beginning of research on the heart muscle."

While still being tested in labs, Duan's proposed therapy gives hope to parents like Robert McDonald, MD, of Jefferson City, Mo. His son Mark was diagnosed with DMD when the boy was 2 years old. Dr. McDonald now serves on the board of directors and the therapeutics committee for Parent Project Muscular Dystrophy, the largest nonprofit organization focused on DMD. Parent Project has also awarded funds for Duan's research.

"He is one of the most valuable people trying to find a solution for DMD," McDonald said. "Parents like me are looking to scientists like him to someday help our children grow up to be men, and hopefully old men."