Hope for patients with a common muscular dystrophy

It is an insidious muscle disease whose symptoms often begin in the mid-teens. Arm weakness and shoulder deformities are common. In some cases, it can lead to hearing loss, abnormal heartbeat and leg weakness. Some patients become severely disabled and wheelchair-bound.

It is one of the most common inherited forms of muscular dystrophy, known as FSHD—facioscapulohumeral dystrophy—named for the muscles of the face, shoulder blade and upper arm it attacks.

FSHD and other muscular dystrophies have proven to be extremely confounding for biomedical researchers, yielding so little information that the very idea of coming up with drugs to treat them has seemed like a dream. For more than two decades, researchers have known that FSHD is caused by a genetic mutation, but no one understood the mechanics of the disease and exactly what was causing the muscles to deteriorate.

Then, after several years of intensive research, a team led by Hutchinson Center neurologist and molecular geneticist Dr. Stephen Tapscott broke through the decades-long stalemate with FSHD. This year, they identified the genes and proteins that damage muscle cells, as well as the mechanisms that can cause the disease.

These discoveries open the door for developing a biomarker-based diagnostic test and future treatments for FSHD—as well as for potential new ways to treat cancer.

Tapscott’s team first showed that it took two genetic changes on chromosome 4 to cause FSHD. Later, they determined that a certain protein called DUX4 —normally found in germ cells that give rise to sperm in males and egg development in females—was abnormally active in muscle cells, causing muscle mayhem.

Because the protein is not supposed to be active in mature muscle tissue, it blocks normal functions and regeneration of muscle cells, leads to muscle cell death, and likely triggers an immune response, with the body attacking its own muscle cells.

With this information in hand and newfound interest from pharmaceutical companies, Tapscott hopes that new therapies and biomarker-based diagnostic tests for FSHD patients are not far off.

“Getting here was not easy,” Tapscott said. “There was not a ‘eureka’ moment, but rather it played out over several years of hard work that gradually revealed the answers. It has been extremely gratifying to put all the different pieces together and see a bigger picture reveal itself that could have a profound impact on patients suffering from this disease.”

In addition, Tapscott’s research has the potential to lead to a vaccine to treat cancer.

One of the major challenges in developing cancer vaccines is finding immune targets present in cancer cells but absent in healthy cells. DUX4, the protein Tapscott identified as the cause of FSHD, induces the expression of proteins that are targeted by the immune system in several types of cancer. Now, he and Dr. Stanley Riddell are working to determine whether they can use DUX4 to stimulate the immune system against these proteins.

“This knowledge gives us a way to manipulate the expression of these proteins, opening the door to developing a new type of vaccine capable of targeting multiple cancers,” Tapscott said.