Objective: To identify a panel of stable DUX4-regulated gene transcripts expressed in affected FSHD muscle biopsies.
Background: FSHD is caused by the pathogenic expression of the homeobox transcription factor DUX4. Aberrant DUX4 expression results in transcriptional dysregulation and activity of a characteristic transcriptional program that causes myofiber death with weakness and accumulation of disability. While pharmacodynamic detection of DUX4 protein and mRNA is challenging, this is not the case for DUX4-regulated gene transcripts which are readily detected in affected muscles (Wang, 2018).
Fulcrum Therapeutics is developing losmapimod, a selective small molecule inhibitor of p38α/β, to reduce aberrant DUX4 expression in FSHD. A preparatory biomarker study was performed to identify a set of stable DUX4-regulated gene transcripts that will provide a pharmacodynamic biomarker endpoint to measure treatment effect on the root cause of FSHD.
Design/Methods: Patients age 18-65, inclusive, with genetically confirmed diagnosis of FSHD1, clinical severity score 2 to 4 and a muscle that meets criteria for biopsy were included in this study. Eligible muscles were identified by MRI STIR+ signal and MFF of 10-40%. Muscle biopsies were performed twice approximately 6 weeks apart on the same leg muscle. Biopsies were analyzed by RNA sequencing. Expression profile data was analyzed by differential expression profiling and machine learning algorithms.
Results: 17 subjects were enrolled and 16 completed the study. Using published RNA sequencing data from a previous study (Wang, 2018) and new RNAseq data from this study, a subset of DUX4-regulated gene transcripts was identified based on consistent detection in repeated biopsies of affected muscles.
Conclusions: We have identified a set of stable DUX4-regulated gene transcripts that provides a pharmacodynamic biomarker endpoint to measure treatment effect on the root cause of FSHD in losmapimod FSHD clinical trials.