Molecules Identified That Target Gene Known to Cause FSHD in Study

Molecules Identified That Target Gene Known to Cause FSHD in Study

Research into molecules that appear to target the gene known to cause facioscapulohumeral dystrophy (FSHD) may lead to a treatment able to slow disease progression, a study reports.

The study, “BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells,” was published in the journal Skeletal Muscle.

In the last decade, research linked the DUX4 gene to FSHD, and the abnormal DUX4 protein it produces that progressively damages skeletal muscles. Drugs targeting the gene’s expression might be able to treat patients.

“DUX4 is not normally produced in adult muscle, and it is toxic when inappropriately expressed in FSHD,” Francis M. Sverdrup, a research fellow in the department of biochemistry and molecular Biology at Saint Louis University, said in a press release.

The researchers aimed to identify molecules that decrease DUX4 expression. To do this, they screened existing drug libraries and then tested the molecules selected on laboratory-grown FSHD skeletal muscle cells.

“Efforts to find drugs for FSHD have lagged behind other forms of muscular dystrophy, likely due to the genetic complexity of the disease,” Sverdrup said. “Now that we know that DUX4 causes the disease, there is a clear molecular target that we can go after. We took advantage of that by setting up these drug screens.”

They identified two classes of drugs that turn off DUX4: one inhibits bromodomain and extra-terminal (BET) proteins, while the other turns on beta-2 adrenergic signaling. These “signaling” medicines, beta agonists, are commonly used to treat asthma.

BET proteins have been shown to play a crucial role in regulating gene expression. Currently, there are five active clinical trials (NCT02157636, NCT01949883, NCT02158858, NCT03068351, NCT02419417) focusing on their potential to treat distinct types of cancers.

“It’s encouraging that our first two screens yielded molecules that turn off DUX4 and this also provides hope that additional candidates can be identified in larger screens,” Sverdrup said.

He is now collaborating with Ultragenyx Pharmaceuticals to possibly develop a FSHD treatment based on this work, the release said.

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