First FSH Muscular Dystrophy High-Throughput Drug Discovery Study Published

Share Article

In research funded by the FSH Society, a patient advocacy organization, a Minnesota team has identified drugs that block the toxic effects of a gene involved in a most common form of muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is among the most common muscle-wasting diseases, affecting more than 500,000 people around the world. Its cause is genetic, passed from generation to generation, although 30 percent of cases arise spontaneously in families with no previous history. There is no treatment, but in a new study published in the journal, Skeletal Muscle on February 1, 2014, researchers have identified dozens of compounds showing early promise for future treatments.

“This is the first published high-throughput drug screening study for FSHD,” noted June Kinoshita, Executive Director of the FSH Society, which helped to fund the research. “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.”

Recent discoveries point to a mysterious protein called DUX4 as a lead suspect in causing FSHD. Normally suppressed in adult muscles, DUX4 is unleashed in FSHD, with toxic effects on muscle cells. In people with FSHD, the facial (facio), shoulder (scapula) and upper arm (humeral) muscles are prone to degenerate, giving the disease its name. FSHD can also affect the lower abdomen and legs, leading to profound disability.

To hunt for drugs that can stop DUX4, the research team, led by Michael Kyba, PhD, of the University of Minnesota, engineered mouse myoblasts (immature muscle cells) to express DUX4 under the control of a genetic switch that is triggered by adding the antibiotic doxycycline to the petri dish.

When DUX4 is switched on, the cells begin to die, and they also become more vulnerable to a variety of chemical insults. Drugs were added to the cultured cells to see if any of them rescued the cells.

The research team tested thousands of compounds on these DUX4-expressing cells, including 1,120 Food and Drug Administration-approved off-patent drugs and 43,000 other chemicals. After extensive studies to weed out false positives, and further winnowing to select compounds with favorable chemical properties, the investigators honed the list to 52 “hits,” or candidates.

“Remarkably, two-thirds of our hits are compounds that protect cells from oxidative stress,” Kyba said. “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.”

Further work is now being planned to understand the precise mechanism behind the anti-DUX4 activity of each of these compounds. This research will help the investigators focus on the most promising ones to develop into therapies. At the same time, each compound can bring to light new insights into how DUX4 causes this devastating disease.

“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,” said Kyba. Additional funding came from the National Institutes of Health, Dr. Bob and Jean Smith Foundation, Friends of FSH Research, the FSHD Global Research Foundation and the Muscular Dystrophy Association.

Reference: Bosnakovski D, Choi SH, Strasser JM, Toso EA, Walters MA, Kyba M (2014) High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity. Skeletal Muscle. 4(1):4.

About the FSH Society
The FSH Society, founded in 1991 by two FSHD patients, is a world leader in combating muscular dystrophy. The non-profit has provided millions of dollars in seed grants to pioneering research worldwide, creating an international collaborative network of patients and researchers. The FSH Society seeks to serve as a source of information and support for all patients and families with FSHD; act as a driving force in the development of research directed towards treatments and ultimately a cure; and bring support to patients and research for FSHD through effective engagement of governmental and private sector organizations and entities. For five consecutive years, the Society has received the Charity Navigator’s four-star rating, the highest distinction held by less than four percent of non-profit organizations in the country. The FSH Society offers a community of support, news and information for FSHD patients and families through its website at For more information about FSHD, please contact the Society at 781-301-6649.

Share article on social media or email:

View article via:

Pdf Print

Contact Author

June Kinoshita

Katherine Bragg
Visit website