Facioscapulohumeral dystrophy clinical trial foundations

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Summary/Abstract Project 2: Facioscapulohumeral Clinical Trial Foundations Project 2 will establish facioscapulohumeral dystrophy (FSHD) clinical trial foundations. The success in identifying the molecular and genetic mechanisms of FSHD provides a strong basis for drug development and therapeutic clinical trials. A major barrier to drug development is lack of validated biomarkers for early phase and proof of concept gene targeted therapies. In addition, the lack of understanding progression over time limits trial design and clinical care. In our prior Wellstone we showed quantitative fat fraction on MRI can demonstrate progression over 1-2 years; with certain MRI features (STIR+, and intermediate fatty involvement at baseline) predicting faster progression rates. The same MRI features also correlated with a basket of FSHD related genes in needle muscle biopsies – including genes related to DUX4 expression, inflammation, and extracellular matrix. Here we plan to extend and expand our foundations for clinical trial preparedness. The broad and long-term goals of this study are to further refine our understanding of MRI as a biomarker by applying artificial intelligence driven automated segmentation and analyses to existing and new long-term follow up data, apply our MRI and molecular biomarkers to a safety and tolerability study of clenbuterol, a drug we identified as inhibiting DUX4 in patient derived cell assays, and using these tools to validate and phenotype a new large mammal model of FSHD type1. This will be accomplished by (Aim 1) extension of the longitudinal clinical study cohorts of FSHD to additional long-term functional and MRI assessments with improved MRI analytic techniques; (Aim 2) perform a prospective 6-month open label multiple ascending dose safety and tolerability study of clenbuterol in FSHD with secondary outcome measures that include functional studies, MRI characteristics, muscle histology, and the muscle molecular signature; and (Aim 3) validating a porcine model of FSHD1 and generating bioresources to support the development of pigs as preclinical models for FSHD. Together, these aims will (1) further validate, refine, and extend clinical, MRI, and molecular measurements of disease activity and progression in FSHD muscles to allow for a better understanding of FSHD progression and the size of change that will be clinically meaningful and ; (2) determine whether clenbuterol is safe and tolerated, and which dose may show preliminary signs of efficacy to support a future phase II clinical trial; and (3) validate a new porcine model of FSHD1 using these functional, MRI, and molecular measurements. The significance of this study is that it will strengthen and extend the foundations for clinical trial design and help hasten therapeutic development for FSHD.