SLU Researcher Draws Bulls Eye Around Muscular Dystrophy Drug Targets
In a recent paper published in the journal Skeletal Muscle, a Saint Louis University researcher reports success in identifying new drug targets
that potentially could slow or halt the progression of a form muscular dystrophy,
an illness characterized by progressive muscle degeneration.
Francis M. Sverdrup, Ph.D., research fellow in the Saint Louis University Department
of Biochemistry and Molecular Biology, studies facioscapulohumeral muscular dystrophy
(FSHD), an inherited type of muscular dystrophy that affects over 800,000 people worldwide.
It often afflicts young adults and typically begins with weakness in the face and
shoulders, then spreads to all skeletal muscles. Currently, there is no cure for FSHD.
Over the course of the last decade, scientists learned that the DUX4 gene is responsible
for FSHD. Inappropriate expression of the encoded DUX4 protein in muscle cells is
the cause of FSHD muscle degeneration.
“DUX4 is not normally produced in adult muscle, and it is toxic when inappropriately
expressed in FSHD,” Sverdrup said.
Sverdrup’s research leverages this discovery by screening existing drug libraries
and testing the drugs on FSHD cells grown in the laboratory.
“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.”
The research team identified two classes of drugs that turn off DUX4. The first are
a class of drugs that inhibit bromodomain and extra-terminal (BET) proteins and the
second are drugs that turn on beta-2 adrenergic signaling (beta agonists). These classes
of drugs already are being studied and utilized for other illnesses; BET inhibitors
currently are being studied in clinical trials for cancer and other diseases while
beta agonists are widely used for asthma and chronic obstructive pulmonary disease.
“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. “Though there are tough odds in drug development, this is
a hopeful finding.”
Sverdrup is working with Ultragenyx Pharmaceuticals, a biopharmaceutical company
focused on the development of novel products for rare and ultra-rare diseases, to
optimize a potential treatment specifically for FSHD.
The research was funded by the NIH/NIAMS (grant R01AR045203), NIH/NINDS (grant P01NS069539),
NIH training grants (T32CA009657, T32GM007270, and T32HG00035), Friends of FSH Research,
FSH Society, FSHD Canada Foundation, Prinses Beatrix Spierfonds (grant W.OP14-01),
and Spieren voor Spieren.
Other researchers on the study include Amy E. Campbell, Jonathan Oliva, Matthew P.
Yates, Jun Wen Zhong, Sean C. Shadle, Lauren Snider, Nikita Singh, Shannon Tai, Yosuke
Hiramuki, Rabi Tawil, Silvère M. van der Maarel and Stephen J. Tapscott.
Saint Louis University School of Medicine
Established in 1836, Saint Louis University School of Medicine has the distinction
of awarding the first medical degree west of the Mississippi River. The school educates
physicians and biomedical scientists, conducts medical research, and provides health
care on a local, national and international level. Research at the school seeks new
cures and treatments in five key areas: cancer, liver disease, heart/lung disease,
aging and brain disease, and infectious diseases.