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.
The charity has previously funded research in the laboratory of Professor Jane Hewitt. This research has led to great advances in our understanding of the evolution of the mutated DNA region and the DUX4 gene across species. This information has improved our knowledge of DUX4 function and the development of potential treatments.
We also funded research in the laboratory of Professor Peter Zammit that highlighted the effects of DUX4 on muscle stem cells and that this protein prevents muscle repair. The funding has led to significant advances in mapping out the differences between FSHD and healthy muscle induced by DUX4, and therefore the identification of a large number of possible therapeutic targets for FSHD. Read the final report on this research project.
The charity currently funds another research project in Professor Zammit’s laboratory that aims to generate a mouse model that will enable to better study the molecular mechanisms underlying FSHD. The team will also use the mouse model to test whether small pieces of genetic material, called molecular patches, could be used to prevent production of the toxic DUX4 protein. This could be a potential therapeutic approach.
We currently also fund research in the laboratory of Dr Linda Popplewell. This project also aims to develop molecular patches that can prevent the production of the DUX4 protein. The molecular patches will be linked to short protein fragments called peptides. These peptides help the molecular patches to get inside cells, thus improving their delivery into muscles.
The charity contributes funding to the ACTmuS study. The ACTmuS study is investigating if a type of psychological therapy, called ACT, can improve quality of life for people with muscle conditions, including FSHD.
We also provide financial support for the establishment and maintenance of a national patient registry. By providing strong links between patients and researchers the registry has the potential to greatly advance our understanding of FSHD as well as keep patients informed about research developments. Read the most recent update on the registry’s progress here.