Peter Jones, associate professor in cell and developmental biology and neurology at University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over a period of three years to develop a research mouse model for facioscapulohumeral muscular dystrophy (FSHD).
Please describe your current research.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies, affecting men and women, children and adults. A major impediment to developing ameliorative treatments for FSHD has been the lack of a viable, robust, and consistent phenotypic FSHD-like animal model. We have addressed this void by generating a novel transgenic mouse model based on the widely accepted paradigm that FSHD is caused by increased somatic expression of the DUX4 gene, which triggers a cascade of events leading to pathophysiology. Thus, the DUX4 mRNA, DUX4 protein, and downstream events are all potential targets for therapeutic development.
Our successfully engineered lines of mice contain the human DUX4 gene in the context of its native gene structure. Initial characterization of these mice indicates that they are healthy and fertile in the absence of inducing DUX4 expression. Induction of DUX4 causes a dose-dependent muscular dystrophy-like phenotype ranging from very mild to very severe. One can imagine that different disease courses may have different applications for therapeutic testing. Therefore, we will determine the precise conditions necessary to develop multiple screenable FSHD-like phenotypes in this mouse model with varying courses of pathology.
Successful completion of this project will provide the FSHD field with valuable tools for understanding the events downstream of DUX4 expression and for preclinical screening of different classes of potential FSHD therapeutics aimed at DUX4 and its downstream targets. It is our hope that enabling this vital step of the therapeutic process will ultimately lead to ameliorative treatments for FSHD.
What inspired you to study FSHD?
When I was a new Assistant Professor at the University of Illinois, a first-year graduate student walked into my office and asked if he could join my lab to study a disease that I had “probably never heard of.” But, he argued, since the disease was thought to be epigenetic in origin and my lab was studying epigenetics, he thought that perhaps we could start working on it together. When I naively asked him “Why?” he told me he had recently been diagnosed with it. That disease was FSHD and he was correct that I had never heard of it, but we soon recognized that FSHD did have a strong epigenetic component and fit within the scope of my lab’s interests, so we started working on it as a side project. This motivated patient got us started in the FSHD field, he earned his Ph.D. in my lab, and now we work full-time on numerous FSHD projects.
What is your area of focus within the FSHD field and why is it important?
Our current focus is on therapeutic development and preclinical testing for FSHD through the development of FSHD-like animal models. To identify potential new therapeutic targets and strategies, we have been studying the factors underlying the epigenetic dysregulation that leads to DUX4 expression in FSHD. In parallel, we have been generating animal models of FSHD for use in screening therapeutic candidates. We now have several different mouse models based on expression of DUX4, the primary mediator of FSHD.
To date, there are no viable phenotypic FSHD-like mouse models based on DUX4 expression. Preliminary data suggests that we have generated such an FSHD-like mouse model, with the goal now being to characterize the benchmarks of the disease course and to refine the conditions needed to render it a suitable and predictable model for preclinical testing. We hope that, once characterized, making this model available to the field at large will help further stimulate FSHD therapeutic development and investment.
Why is it important that MDA continue to fund research in FSHD?
FSHD is far more common than was once thought and is underfunded compared to other muscle diseases. In addition, the FSHD field as a whole has gained considerable momentum recently. With new groups, new ideas, and new approaches coming into the field, it is vital that funding keeps pace with the advances in research.
What do you feel people impacted by FSHD can have the most hope about with respect to research right now?
After many years, the pathogenic mechanisms in FSHD are finally becoming clear and the field now has viable therapeutic targets which are under active investigation. These advances have stimulated growing interest from pharmaceutical companies, which have targeted FSHD as a good investment. A phenotypic animal model has been a gaping hole in the preclinical testing pipeline, but successful completion of this project should greatly help to fill that need.
Does your work have any potential implications for other disease fields?
I feel that an advancement in the understanding or treatment of any muscle disease is really an advancement for all. Therapeutic strategies are likely to be widely applicable, from PMOs and AAV-mediated antisense approaches to drug inhibition or CRISPR/Cas9 platforms. While specific details of therapy may vary from one disease to another, advances in the delivery and effectiveness of these approaches will be beneficial almost across the board. Likewise, we anticipate that our FSHD-like mouse models will stimulate advances focused on FSHD that could ultimately prove beneficial for other diseases as well.