ID of Utrophin Brake Raises DMD Treatment Hopes

MDA-supported researchers at the University of Pennsylvania and the University of Ottawa report finding a molecule that keeps the muscle protein known as utrophin confined to one small area of a muscle fiber and thereby limits its potential as a therapy for Duchenne muscular dystrophy (DMD). Blocking this “braking” molecule could become a strategy for treating the disease.

MDA grantee Tejvir Khurana at the University of Pennsylvania and colleagues, including MDA-supported Bernard Jasmin at the University of Ottawa, say a compound called ERF (ETS-2 repressor factor) helps regulate utrophin production in mature muscles.

The utrophin protein is very similar in structure to the dystrophin protein, which is missing in boys with DMD. However, its instructions are in a gene on chromosome 6, in contrast to those for dystrophin, which are on the X chromosome and are defective in DMD-affected animals and people. The utrophin gene is not affected in DMD.

During fetal development and up until shortly after birth, utrophin is produced (expressed) all around muscle fibers. But as the fibers mature, most of the utrophin is replaced by dystrophin, except in the small areas where the nerve and muscle fibers meet, called the neuromuscular junctions.

Figuring out a strategy for returning utrophin expression to the whole muscle fiber has been a goal of MDA-supported research ever since experiments in mice in the 1990s showed that utrophin can at least in part compensate for dystrophin deficiency.

Increasing utrophin’s presence might in some situations be easier than replacing or repairing dystrophin genes. And, utrophin would be highly unlikely to cause an unwanted immune response, since boys with DMD already make some utrophin.

The investigators, who published their findings online May 16 in Molecular Biology of the Cell, say ERF apparently interacts with a molecular switch (promoter) to repress the activation of utrophin instructions. When they reduced ERF levels, utrophin promoter activity and utrophin expression outside the neuromuscular junctions increased.

“Together, these studies suggest ‘repressing repressors’ as a potential strategy for achieving utrophin upregulation (increase) in DMD,” the researchers say.

“Dr. Khurana's work hints at what could be an important new drug target for Duchenne,” said Sharon Hesterlee, MDA’s vice president of Translational Research. “The more options we have with this disease, the better.

“We’ve known for a while that increasing utrophin expression can reduce symptoms of the disease, but it’s very difficult to use a drug to increase gene activity. What’s nice about this work is that now we can try to ‘block a blocker’ to get the same effect. It’s a more drug-friendly approach.