Spring/Summer 2018
Doctor, Heal Thyself

synapse: University of Nevada, Reno School of Medicine

Ryan with lab hood

Ryan Wuebbles, Ph.D., research assistant professor, is reflected in his fume hood. Wuebbles is working to cure FSHD-the same disease weakening his own body. Photo by Brin Reynolds.

UNR Med researcher part of team dedicated to curing his disease

Story by Jessica Santina

A team of researchers at the University of Nevada, Reno School of Medicine are working feverishly, with the help of a one-year grant, to develop a treatment for muscular dystrophy. None of them has more at stake than Ryan Wuebbles, Ph.D., who himself is battling Facioscapulohumeral Muscular Dystrophy (FSHD) and racing against the clock to cure his own disease.

Wuebbles, a research assistant professor in UNR Med's Department of Pharmacology, was diagnosed with FSHD at age 20. Now 39, Wuebbles works alongside Dean Burkin, Ph.D., director of the Cellular Molecular Pharmacology and Physiology graduate program, along with the Peter and Takako Jones Lab, to develop revolutionary treatments for muscular dystrophies, including FSHD.

Wuebbles was a sophomore studying electrical engineering at the University of Illinois, Urbana-Champaign, when he received his diagnosis, though his symptoms began at age 12.

"As a kid, I was very athletic," Wuebbles said. "But when I was 12, I realized I couldn't do a sit-up anymore. I did a lot of heavy weightlifting in college, and my shoulder blades were sticking out way too much when I was doing certain exercises."

A trip to the neurologist and a blood test quickly confirmed he had FSHD, a progressive disease involving the deterioration of the facial, scapular and humeral muscles. Though not usually fatal, the muscle degeneration can eventually make simple movements - walking, lifting the arms and even smiling - difficult or even impossible as time goes on. Wuebbles decided immediately to focus his education on work that could change his own life and those of others with FSHD.

"I wanted a field in which I could continue to do work I found interesting and on my own disease, but also where I could eventually mainly sit and work at my computer out of necessity," Wuebbles said, adding that he had always preferred his biology classes anyway and knew this was a better fit than engineering.

Wuebbles decided to pursue a doctoral degree in biology at Illinois, where Peter Jones, Ph.D., had just joined the faculty and, along with his wife, Takako Jones, Ph.D., was doing exciting research into epigenetics - biological processes that alter gene expression - which is believed to play a role in FSHD. Jones was looking for student researchers, and Wuebbles joined up, convincing Jones to incorporate FSHD into his research.

"It's the most complicated genetic human disease you can work on," Wuebbles said, explaining that FSHD is caused by aberrant expression of the DUX4 gene. With few exceptions, DUX4 expression is typically silenced in all tissues, but is extremely toxic to muscle in FSHD patients when the loss of epigenetic repression allows it to be expressed.

After studying the cause of FSHD in frog models, Wuebbles earned his Ph.D. in 2009. Peter Jones encouraged him to learn how to conduct small molecule assays and mouse model studies, but to stay within the muscular dystrophy field. At that time, no valid mouse model was available for FSHD, but it was clear that the field would need one to move therapeutics from the bench to the bedside.

Luckily for Wuebbles, Dean Burkin, Ph.D., a professor in UNR Med's Department of Pharmacology, had an opening for a post-doc in 2009 and was conducting pioneering studies on LAMA2 congenital muscular dystrophy (LAMA2-CMD). Coincidentally, Wuebbles, Jones and Burkin all had known each other briefly at the University of Illinois in 2002.

As a post-doc with Burkin, Wuebbles helped assay small molecule enhancers for Alpha-7 (α7) integrin, a protein known to be involved in muscle regeneration and a modifier of disease progression in mdx mouse models for Duchenne Muscular Dystrophy (DMD). In 2012, the University filed for a U.S. patent on their discovery, and by 2013, the two scientists had formed Strykagen, a biopharmaceutical company that could spearhead efforts to move these therapies toward the clinic. In 2017, Burkin and Wuebbles published a study on the use of one of these small molecules, called SU9516, in successfully slowing disease progression in the mdx mouse model. Coming full circle, Peter and Takako Jones arrived at the University in 2017, bringing with them a novel DUX4-expressing FSHD mouse model that they had created. Thus Burkin, the Joneses and Wuebbles began testing muscle-regenerating therapeutics for the treatment of FSHD patients.

The success of this DMD treatment research has been encouraging both at the School of Medicine and around the world. In February 2016, the Peter and Takako Jones Lab, which at the time was located at the University of Massachusetts Medical School, received a $300,000, three-year Muscular Dystrophy Association research grant to develop an effective mouse model for FSHD research. Then, in February 2018, Wuebbles and Takako Jones were awarded a one-year, $190,000 grant from the FSH Society to test the effectiveness of Stryka-001 (another α7 integrin-enhancing small molecule) in the FSHD mouse model.

As Wuebbles explains, two FSHD mouse studies are included in the grant: a short-term treatment study, involving a single round of DUX4 expression in muscle; and a chronic treatment study, in which multiple rounds of DUX4 expression are induced. Wuebbles and Takako Jones are assessing whether treatments with Stryka-001 ameliorates the FSHD-like dystrophic disease progression relative to controls. At the time of this writing, the chronic study was underway, and the researchers were close to beginning the short-term study. Wuebbles indicated that, so far, the mice were responding well to the therapy and their strength was improving.

"We are all working together exactly as we planned [at Illinois]; the Burkin lab has expertise in dystrophic mice and has developed potential therapeutics that need to be tested. The Jones lab is a leading lab for FSHD research and has a deep understanding of the disease mechanism," said Takako Jones. "Any benefit to the muscle is welcome to patients. It is a slowly progressing disease, but FSHD patients eventually lose the ability to do basic, everyday activities. If we can slow the progress of this disease a little further, like adding five more years to their walking ability, it will make a huge difference in their quality of life."

As senior associate dean for research at UNR Med, Bill Gerthoffer, Ph.D., actively supports and promotes biomedical research taking place at the University.

"This project is really novel and important for the FSHD community, a small but essentially untreatable set of adult patients with muscular dystrophy," Gerthoffer said. "This work offers some really exciting hope for everyone afflicted. They're in the early mouse model stage, but one of our strategic plans is developing an internationally recognized center for muscular dystrophy research at UNR. We're all working toward that here on campus, and Renown is getting involved, with interest from pediatricians there as well."

Meanwhile, Wuebbles' disease continues its slow progression. Now married with two sons, he currently remains in good health, though he now uses a cane. He's excited to be part of such important research, regardless of the outcome.

"It's pretty realistic to think that in eight months to a year we'll be in the clinical trial process," Wuebbles says. "It's big for me and for the University. The success of the therapeutics may somewhat determine where my career goes, obviously. But no matter what, it's been a great experience. I've learned a ton and it's been a great choice on my part to come to UNR Med."