Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies

Area of Science:

• Biomedical research
• Muscle pathology
• Genetics

Background:

• Facioscapulohumeral dystrophy (FSHD) pathophysiology understanding advances candidate therapeutics.
• Identifying disease activity markers is crucial for clinical trial design.
• DUX4 expression is a potential drug activity marker, but not consistently found in FSHD muscle biopsies.

Purpose of the Study:

• To assess the stability of MRI characteristics and gene expression markers over one year in FSHD patients.
• To identify reliable biomarkers for FSHD disease activity and progression.
• To evaluate the utility of DUX4-regulated genes, inflammation, extracellular matrix, and cell cycle genes as potential therapeutic response indicators.

Main Methods:

• One-year follow-up study involving repeat MRI and muscle biopsies in FSHD patients.
• Analysis of DUX4-regulated genes, inflammation, extracellular matrix, and cell cycle gene expression.
• Comparison of gene expression between MRI T2-STIR positive and negative muscle tissues.
• Subgroup analysis based on gene expression patterns.

Main Results:

• MRI T2-STIR positive muscles consistently showed higher expression of DUX4-regulated genes, inflammation, extracellular matrix, and cell cycle genes.
• Gene expression profiles remained largely stable over the one-year follow-up period, with individual variability.
• Pooled data identified FSHD subgroups and a gene set distinguishing FSHD from controls, including DUX4-target, inflammatory, immune, and cell cycle genes.

Conclusions:

• MRI T2-STIR positivity correlates with specific gene expression signatures in FSHD.
• A defined set of genes (DUX4-target, inflammatory, cell cycle) may serve as candidate biomarkers for FSHD activity and progression.
• Further validation in independent datasets is required for these candidate markers to be used in clinical trials for disease monitoring and therapeutic response assessment.