Inaugural Dean’s Distinguished Seminar Explores Treatments for Muscle Disease

The University of Arizona College of Medicine – Phoenix hosted the inaugural Dean’s Distinguished Seminar, a lecture series intending to provide a platform for outstanding researchers in the biomedical field to highlight their research.

“Although our dean [Fred Wondisford, MD, MS, MBA] is distinguished, it is the distinguished speakers that the event title is referring to,” said Chris Glembotski, PhD, director of the Translational Cardiovascular Research Center and vice dean for the Office of Research at the U of A College of Medicine – Phoenix.

Eric Olson, PhD, served as the series’ first speaker. Dr. Olson is a professor and founding chair of the Department of Molecular Biology at the University of Texas Southwestern Medical Center. He has had more than 300 publications in high impact peer-reviewed journals and his work has been cited more than 200,000 times. 

And, in addition to his accomplishments as a scientist, Dr. Olson is a musician. His band is named the Transactivators, referring to proteins that turn genes on and off. He also has played as a member of legendary country singer Willie Nelson’s group and has a friendship with the singer.

Recently, his laboratory pioneered a gene-editing approach that corrects most Duchenne muscular dystrophy (DMD) mutations.

For the Dean’s Distinguished Seminar, Dr. Olson presented “Muscle Making and Muscle Breaking: From Development to Disease and Beyond.” It shared insights into the molecular basis of cardiovascular development and provided the latest updates on gene editing strategies for the correction of genetic disorders of both the muscle and the heart.

“Muscle provides the meaning to the wonders of life,” Dr. Olson said. “Every breath you take, every move you make, is controlled by muscle.”

Dr. Olson further discussed the history of DMD and how it affects the body. First discovered by French neurologist Guillaume Duchenne in the 1860s, DMD is a progressive, genetic neuromuscular disorder caused by mutations to the DMD gene. This results in a dysfunction of the dystrophin protein.

Affecting roughly 1 in 3,500 male births, there are approximately 300,000 men and boys struggling with DMD.

“The disease is typically identified around the age of two when a young boy will have difficulty keeping up with his playmates or getting up the stairs,” Dr. Olson said. “Ultimately, they lose the use of their arms and become confined to a ventilator because the diaphragm fails.”

While there is much research being done to treat the disease, so far there has not been an effective therapy to eradicate it. However, Dr. Olson and his trainees discovered core transcription factors governing cardiac and skeletal development and disease, reshaping cardiovascular and muscle biology and enabling therapeutic strategies.

Myocardin, a key regulatory protein, controls muscle gene expression by forming nuclear condensates that cluster together in the cell nucleus. 

“Myocarditis sits at the foundation of all smooth, cardiac muscle cells because it activates the transcription of the global program of cardiovascular development,” Dr. Olson said. 

From using an advanced gene editing technology called CRISPR, Dr. Olson and his team were able to stop the progression of DMD in preclinical model and human cells.

“We want to push further through what’s known as base editing, which does not involve the creation of a double-stranded DNA break or precise edit,” Dr. Olson said. “We are continuing to optimize gene editing, but we’re also looking for alternative strategies.”

After learning that serum response factor plays a role with myocarditis in terms of switching the activation domain, there remains a mystery of unique methods to treat DMD that have yet to be explored.

“What might be the role of this unique condensate-forming domain in response to disease-signaling or mutations?” Dr. Olson said. “Do the myocardial-related proteins that have a myriad of roles in other muscle cell types use similar or different strategies?”

With more work, Dr. Olson and his laboratory are hopeful that more approaches can be optimized to treat DMD.