Facioscapulohumeral Dystrophy Clinical Trial Foundations

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PROJECT 2 - ABSTRACT Previously, we have established a correlation between muscle function, histopathology, MRI imaging characteristics, and candidate molecular biomarkers. This proposal will extend the original study to further refine the temporal relationship of MRI abnormalities, tissue pathology, RNA biomarkers, and disease progression; validate these correlations in an independent FSHD cohort and extend these studies to include DNA methylation; and determine whether immune cell molecular phenotyping identifies an oligoclonal T-cell expansion in FSHD muscle. This will be accomplished by three aims. Aim 1 will extend our previous longitudinal biomarker clinical study of FSHD to determine correlations with disease progression. Individuals with FSHD have slowly progressive weakness that requires at least 12 months to demonstrate significant decline in overall muscle strength. In this aim we will extend our original study to determine the predictive value of different measures of disease activity. Aim 2 will include a third clinical study site to validate and expand molecular and imaging correlations and determine the relationship to disease progression. Collection of a validation data set is essential to understand the true predictive power of associations between the MRI findings, muscle pathology, and RNA biomarkers suggested from our prior study. Additionally, the degree of DNA methylation at the DUX4 locus will be determined to examine its relation to the rate of disease penetrance and progression. Aim 3 will perform a molecular analysis of the inflammatory response in FSHD muscle. Our prior study of MRI and muscle biopsy in FSHD shows a correlation of STIR+ signal with an inflammatory cell infiltrate in FSHD. This aim will determine the molecular phenotype of the infiltrating cells, their clonal complexity, and the sequence of any dominate T-cell receptor sequences. The significance of this study is that it will identify and validate measurements that predict disease activity and progression in FSHD muscles that will inform rigorous trial design for future therapeutic trials.