Results in Canine Model Show Potential for Muscular Dystrophy Gene Therapy

A team of immunologists and molecular biologists has demonstrated in a canine model a gene therapy method for treating Duchenne muscular dystrophy (DMD) that is able to penetrate all muscles in the body.

Duchenne muscular dystrophy (DMD) is one of the most common lethal muscle diseases. This X-linked recessive genetic disease is caused by a dystrophin gene mutation and the subsequent lose of dystrophin protein. Dystrophin is a rod-shaped cytoplasmic protein and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. Normal muscle tissue contains small amounts of dystrophin (about 0.002% of total muscle protein), but its absence leads to both DMD and fibrosis, a condition of muscle hardening.

Investigators at the University of Missouri (Columbia, USA) previously had shown that it was possible to use an adeno-associated virus (AAV) as the vector to transport the dystrophin gene and bring about body-wide transduction of muscle tissue in a rodent model. However, follow-up experiments with a canine model failed due to a strong cellular immune response.

Now, in a paper published in the September 30, 2008, issue of the journal Molecular Therapy the investigators reported that in neonatal dogs they observed robust skeletal muscle transduction throughout the body after a single intravenous injection. Systemic transduction was achieved in the absence of drugs or immune suppression, and it lasted for at least six months (the duration of study).

"Between 40% and 60% of the body weight is muscle, so it is vital that we find a way to deliver the therapy to every muscle in the body,” said senior author Dr. Dongsheng Duan, associate professor of molecular microbiology and immunology at the University of Missouri. "Since dogs are 250 times the size of mice, but only nine times smaller than a human on average, we have taken a significant step in understanding if this therapy can work.

"The difficult challenge with treating Duchenne muscular dystrophy, and other types of muscle-related diseases, is that the therapy must reach almost every muscle throughout the body,” Dr. Duan said. "We have found that our new therapy, which uses a particular virus to deliver the gene therapy, reaches all of the muscles in large animals. This development raises the hope of whole body correction of Duchenne muscular dystrophy. If you can treat an infant before they develop symptoms, you can treat the patient before they experience muscle loss. If you wait until symptoms start to appear, the muscle has already started to deteriorate. It is very difficult to treat when there is no muscle there.”

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