The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 2019
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 β-2 adrenergic receptor suppress DUX4 expression by activating adenylate cyclase to increase cAMP levels. ⋯ 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.