By Fran Sverdrup, PhD, Associate Professor, Department of Biochemistry and Molecular Biology at Saint Louis University.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy. The name itself offers important insights about how the disease affects patients, involving a striking pattern that begins with weakening in the muscles of the face and progresses to affect muscles in the shoulder girdle and upper arms. Muscle degeneration remains progressive and typically spreads to nearly all skeletal muscle groups over the course of years to decades.
Epigenetic Cause
Unlike many rare diseases, FSHD is unique in that we fully understand its cause. The culprit: gain of function mutations that result in “turning on” a gene known as DUX4 in skeletal muscle where it should not be present (Tawil et al. 2014). The DUX4 gene plays a role in fetal development but in most people it is “turned off” at birth. In people living with FSHD, DUX4 expression continues throughout their lives. Based on the understanding of this genetic aberration, the discovery of a clear molecular target has ignited the search for what could be a first-of-its-kind treatment option for FSHD, with important progress made in recent years.
Pathway to a Potential Treatment
To identify an effective treatment for FSHD, one of the most attractive options is to identify a drug that “turns off” the DUX4 gene, thus targeting the root cause of the disease. While this goal seemed unachievable even a few years ago, advances in understanding of the mechanism of action of DUX4 and the ability of p38 MAP kinase inhibitors to regulate the expression of this gene have opened new avenues of research. p38 inhibitors have been shown to effectively turn off DUX4 expression in patient muscle cells in culture and in a mouse model of FSHD gene regulation (Oliva et al. 2019).
Do we have to turn DUX4 completely off? While it is not clear how much of a reduction in DUX4 will be needed to elicit a clinically meaningful benefit to patients, studies of healthy people (without FSHD) that express low levels of DUX4 are informative. The existence of a subset of non-FSHD individuals that express low levels of DUX4, but do not show clinical symptoms, suggests that we do not need to turn DUX4 completely off (Jones et al. 2012, Jones et al. 2015). Treatments that reduce DUX4 expression, therefore, have great potential to modify the clinical symptoms of FSHD.
What makes p38 a good drug target? One requirement for any degenerative muscle disease is that a treatment not affect the regenerative healing process in muscle cells. Available p38 inhibitors target p38α and p38β two highly related enzymes that are both expressed in muscle cells. In mouse models, deleting p38β has been shown to have no discernible effect on muscle (Ruiz-Bonilla et al. 2008). With deletion of p38α muscles grow and function normally but with slightly delayed myofiber growth and maturation. Muscle progenitor cells are actually increased in these mice, providing a potential therapeutic advantage in dystrophic muscle where progenitors are typically reduced (Brien et al. 2013). Regarding FSHD specifically, human FSHD muscles cells that have been transplanted into mice differentiate normally when the mice are treated with p38 inhibitors at a level that suppresses DUX4 expression. Collectively, these findings provide strong support to explore the use of p38 inhibitors to turn off DUX4 expression and potentially improve muscle health in FSHD patients.
Despite many important advances in research, our understanding of the role that p38 kinase plays in turning on the DUX4 gene in FSHD patient muscles remains limited. The regulation of DUX4 (turning it on or off) turns out to be a highly complex problem that we are only beginning to solve. In its relatively short history, FSHD research first focused on understanding static differences between normal and FSHD muscles cells. Tremendous effort by many scientists has illuminated the critical role of epigenetics: the changes in specific regulatory features around the DUX4 gene that keep it turned off in normal muscle that are lost in FSHD. But that is only part of the story. Turning on a gene requires not only the loss of the features that keep the gene turned off, but also additional specific signals to turn the gene on. p38 potentially promotes both processes.
Ongoing Research
A clinical research program sponsored by Fulcrum Therapeutics for an investigational selective p38α/β inhibitor called losmapimod has advanced to a Phase II clinical trial with data expected later in 2020. While additional research is necessary to better understand the complex circuitry within FSHD muscle cells and the genetic factors that turn off and turn on the expression of DUX4, the identification of p38 as an influencer of the gene’s expression is an important step forward.
Clinical Trial Information
Please visit Clinicaltrials.gov to research clinical trials currently underway.
Resources
Brien, P., D. Pugazhendhi, S. Woodhouse, D. Oxley and J. M. Pell (2013). “p38alpha MAPK regulates adult muscle stem cell fate by restricting progenitor proliferation during postnatal growth and repair.” Stem Cells 31(8):1597-1610.
Jones, T. I., J. C. Chen, F. Rahimov, S. Homma, P. Arashiro, M. L. Beermann, O. D. King, J. B. Miller, L. M. Kunkel, C. P. Emerson, Jr., K. R. Wagner and P. L. Jones (2012). “Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis.” Hum Mol Genet 21(20):4419-4430.
Jones, T. I., O. D. King, C. L. Himeda, S. Homma, J. C. Chen, M. L. Beermann, C. Yan, C. P. Emerson, Jr., J. B. Miller, K. R. Wagner and P. L. Jones (2015). “Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy.” Clin Epigenetics 7:37.
Oliva, J., S. Galasinski, A. Richey, A. E. Campbell, M. J. Meyers, N. Modi, J. W. Zhong, R. Tawil, S. J. Tapscott and F. M. Sverdrup (2019). “Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy.” J Pharmacol Exp Ther 370(2):219-230.
Ruiz-Bonilla, V., E. Perdiguero, L. Gresh, A. L. Serrano, M. Zamora, P. Sousa-Victor, M. Jardi, E. F. Wagner and P. Munoz-Canoves (2008). “Efficient adult skeletal muscle regeneration in mice deficient in p38beta, p38gamma and p38delta MAP kinases.” Cell Cycle 7(14): 2208-2214.
Tawil, R., S. M. van der Maarel and S. J. Tapscott (2014). “Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.” Skelet Muscle 4:12.