Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by misexpression of the double homeobox 4 (DUX4) developmental transcription factor in mature skeletal muscle, where it is responsible for muscle degeneration. Preventing expression of DUX4 mRNA is a disease-modifying therapeutic strategy with the potential to halt or reverse the course of disease. We previously reported that agonists of the -2 adrenergic receptor suppress expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 mitogen-activated protein kinase as a major regulator of expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress expression in FSHD type 1 and 2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual small interfering RNA-mediated knockdown of either p38 or p38 suppresses expression, demonstrating that each kinase isoform plays a distinct requisite role in activating Finally, p38 inhibitors effectively suppress expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38 and p38 isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD. SIGNIFICANCE STATEMENT: Facioscapulohumeral muscular dystrophy (FSHD) currently has no treatment options. This work provides evidence that repurposing a clinically advanced p38 inhibitor may provide the first disease-modifying drug for FSHD by suppressing toxic DUX4 expression, the root cause of muscle degeneration in this disease.