P.43Targeting DUX4 expression, the root cause of FSHD: identification of a drug target and development candidate

Abstract

FSHD is disabling muscular dystrophy characterized by descending progressive skeletal muscle weakness affecting the face, shoulders, arms and trunk, followed by weakness of the distal lower extremities and pelvic girdle. There are currently no approved treatments for the disease. When DUX4, a homeobox transcription factor normally expressed during embryogenesis, is expressed in post-natal skeletal muscle, it results in apoptosis and replacement of the muscle by fat, leading to the clinical manifestation of disease. Using patient-derived myotubes, we employed our target identification strategies to identify p38α MAPK as a tractable target that reduces DUX4 expression. In further preclinical validation experiments using both pharmacological and genetic tools, we observed that target inhibition leads to a reduction of DUX4 mRNA and protein, expression of downstream DUX4 target genes and inhibition of apoptosis of FSHD myotubes. Moreover, reduction of DUX4 expression via p38α inhibition appears to be genotype independent, as observed by a significant effect in both FSHD1 and FSHD2 patient-derived myotubes. RNA-seq profiling indicates a selective effect on the DUX4 transcriptional program without impacting myogenesis. Supported by preclinical data and extensive human experience outside FSHD, we have selected the p38α/β inhibitor losmapimod for development in FSHD. PK/PD studies in mice and rats indicate that losmapimod distributes to the muscle rapidly and engages the p38 target at concentrations that we believe may be achieved in the clinic.