Establish a whole-body MRI imaging protocol and analysis algorithms to measure replacement of skeletal muscle tissue by fat in FSHD.

FSHD is caused by loss of repression at the D4Z4 locus resulting in aberrant expression of the homeobox transcription factor DUX4. DUX4 activates a downstream transcriptional program resulting in skeletal muscle loss and motor disability characterized by slowly progressive descending weakness.  Clinical severity, ambulation, and muscle strength are strongly correlated with muscle fat fraction (MFF) as measured by musculoskeletal fat-water separated MRI (MSK-MRI).  There is little established consensus on standards for repeatability, reproducibility, and measurement error in whole-body MSK-MRI targeting individual muscles (WB-MSK-MRI) for multicenter clinical trials. Fulcrum Therapeutics is developing losmapimod, a selective small molecule inhibitor of p38α/β to reduce DUX4 expression, the root cause of FSHD. It is expected that an effective treatment for FSHD will reduce or arrest progression of replacement of muscle by fat and loss of muscle tissue. We performed a preparatory biomarker study to evaluate, optimize and standardize a WB-MSK-MRI protocol for losmapimod trials.   

Seventeen adults with FSHD1 aged 18 to 65 were enrolled at 6 sites.  Sixteen completed the study and were imaged twice 4 to 12 weeks apart.  Volumetric analysis of eighteen different individual muscles or muscle groups from shoulder, proximal arm, trunk and legs were performed bilaterally.  Outcomes measured included: lean muscle volume (LMV), muscle fat infiltration (MFI), and MFF.

All but one patient tolerated the repeated MRI protocol well.  Measurement of total LMV (Pearson’s r=0.9984), MFI (r=0.9845) and MFF (r=0.9918) showed strong correlations between the two timepoints.