LEXINGTON, Mass.—A team of researchers has made an encouraging discovery for patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscle-wasting diseases: several dozen compounds that could hold promise as future treatments.
The work focused largely on a protein known as DUX4, which is a primary suspect as the cause of FSHD. While the protein is usually suppressed in adult muscles, it is active in FSHD, which causes cells to become more vulnerable to a range of chemical insults and to begin dying. The scientists, led by Dr. Michael Kyba of the University of Minnesota, engineered mouse myoblasts—immature muscle cells—that would express DUX4 under the control of a genetic switch, which could be triggered by adding doxycycline, an antibiotic, to the Petri dish. Drugs were then added to the cultured myoblasts to see if any were capable of rescuing the damaged cells.
All told, the scientists tested thousands of compounds, including 1,120 off-patent drugs approved by the U.S. Food and Drug Administration and 43,000 other chemicals. Once the team eliminated false positives and selected for compounds that displayed favorable chemical properties, they ended up with 52 potential candidates.
“Remarkably, two-thirds of our hits are compounds that protect cells from oxidative stress. Although we need to be cautious extrapolating from cells in a dish to human patients, I am enthusiastic about testing whether protecting cells from oxidative stress is beneficial in FSHD,” said Kyba in a news release about the findings.
“We were very, very fortunate to get support from the FSH Society in the form of a postdoctoral fellowship back in the dark ages when nobody else was funding research on DUX4,” he added.
“This is the first published high-throughput drug screening study for FSHD,” said June Kinoshita, executive director of the FSH Society, which helped fund the study. “Years of investment in basic research to understand the genetic mechanism of the disease and to develop cell-based assays have made it possible to carry out this efficient strategy to identify drug candidates.”
FSHD is characterized by the facial, shoulder and upper arm muscles being prone to degeneration, though the disease can also affect the lower abdomen and legs. More than 500,000 people worldwide are afflicted with FSHD. The disease is genetic, though 30 percent of FSHD cases are seen in families that display no previous history. No drugs exist that treat FSHD at its source, says Kinoshita, who explains that the best option for patients currently is symptomatic relief, via physical therapy or pain medication.
Though FSHD is one of the most common muscular dystrophies, Kinoshita tells DDNews that historically it has received very little research funding until about 20 years ago, when the FSH Society was founded. “As a result of the advocacy work of the FSH Society, we were able to get Congress to allocate NIH funding for all of the muscular dystrophies, including FSHD, and that’s what has made the difference,” she adds.
“The role of patient advocacy organizations is absolutely critical,” Kinoshita affirms. “Without them there would not be research on many of the rare diseases.”
“Many scientists think DUX4 is the cause of FSHD, while others think the story is more complex, but there is a consensus that DUX4 is an important player. This is a small field but it has had huge accomplishments. Since the genetic mechanism was identified in 2010, there has been an explosion of research on anti-DUX4 therapies and also on other drug targets around the DUX4 regulatory pathways,” she says. Kyba’s work looked promising to the FSH Society given his development of a cell line for screening drugs as well as “a relevant assay that could look at drugs for toxicity.”
Moving forward, further research is in the works to elucidate the mechanism behind the compounds’ anti-DUX4 activity, which will help to determine how DUX4 causes FSHD as well as which of the 52 promising compounds has the most potential.
The study, “High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity,” appeared Feb. 1 in the journal Skeletal Muscle. Additional funding for the work came from National Institutes of Health, the Dr. Bob and Jean Smith Foundation, Friends of FSH Research, the FSHD Global Research Foundation and the Muscular Dystrophy Association.