The X-linked genetic disease, muscular dystrophy, affects the structure and function of skeletal muscles. Muscular dystrophy patients harbor mutations in a gene that encodes a protein known as dystrophin. Dystrophin attaches the internal skeleton of skeletal muscle cells to the cell membrane. In turn, proteins in the skeletal muscle membrane attach to the intracellular matrix that acts as the foundational material upon which muscle cells (and other cells) sit. Therefore, the dystrophin protein serves to attach skeletal muscle cells to the extracellular matrix. The loss of dystrophin causes muscles to separate from the cell matrix and detach from each other. The lack of attachment of muscles to each other causes them to degenerate and die.
The death of skeletal muscles in muscular dystrophy patients leads to the replacement of what was once skeletal muscle with scar tissue, fatty tissue, or even bone. Because muscular dystrophy is caused by mutations in an X-linked gene, the majority of muscular dystrophy patients are boys. The losses of muscle structure, function, and mass cause patients to lose their ability to walk and eventually breath (since the diaphragm is a skeletal muscle) as they age. Thus muscular dystrophy tends to put patients in wheelchairs and condemn them to respirators.
The most common form of muscular dystrophy is called Duchenne Muscular Dystrophy or DMD. Close to 250,000 people in the United States suffer from muscular dystrophy. Treatment options are very limited and usually palliative. However, a research team from the University of Missouri has successfully treated dogs that suffer from DMD. They are optimistic that human clinical trials can be planned in the next few years.
This is a remarkable finding, especially, when you consider that the dystrophin gene is extremely large. In fact, the dystrophin gene is the largest gene in the human genome. This makes gene therapy treatments for DMD problematic.
Dongsheng Duan, who serves as the lead scientist in this study, and is the Margaret Proctor Mulligan Professor in Medical Research at the MU School of Medicine “This is the most common muscle disease in boys, and there is currently no effective therapy. This discovery took our research team more than 10 years, but we believe we are on the cusp of having a treatment for the disease.
Duan continued: “Due to its size, it is impossible to deliver the entire gene with a gene therapy vector, which is the vehicle that carries the therapeutic gene to the correct site in the body,” Duan said. “Through previous research, we were able to develop a miniature version of this gene called a microgene. This minimized dystrophin protected all muscles in the body of diseased mice.”
Duan and his colleagues worked for almost ten years to develop a viable strategy that can safely transfer the micro-dystrophin gene to every muscle in a the body of dogs that have a canine form of DMD. Dogs are an excellent model system for human medicine, since dogs are about the same size as a human boy. Successful treatment of DMA dogs can provide the foundation for human clinical trials.
In this new study, Duan and his team demonstrated that by using a common virus to deliver the micro-dystrophin gene to all the muscles in the body of a diseased dog. Duan and others injected DMA dogs with this genetically engineered virus when they were two-three months old. For dogs, this is about the time when they begin to show some of the DMD-associated signs and symptoms. Now, these dogs are six-seven months old and they are experiencing normal development and muscular activity.
“The virus we are using is one of the most common viruses; it is also a virus that produces no symptoms in the human body, making this a safe way to spread the dystrophin gene throughout the body,” Duan said. “These dogs develop DMD naturally in a similar manner as humans. It’s important to treat DMD early before the disease does a lot of damage as this therapy has the greatest impact at the early stages in life.”