Biomarker development to support the clinical development of utrophin modulators for Duchenne muscular dystrophy therapy

The continual expression of utrophin protein by pharmacological maintenance of utrophin transcription in dystrophin deficient muscle fibres is a potential disease modifying treatment for Duchenne muscular dystrophy (DMD). In order for proof of concept of utrophin modulators to be demonstrated in DMD patients, a multicomponent biomarker strategy has been instigated to quantify utrophin levels and demonstrate evidence of reduced muscle fibre regeneration. To demonstrate an increase in utrophin derived from drug treatment above the natural levels resulting from regeneration, we aim to quantify both fibre numbers and levels of utrophin protein localised to mature fibres in pre- and post-dose muscle biopsies. To determine a reduction in the rate of degeneration, i.e. increase in mature fibre survival, changes in the percentage of regenerating fibres, determined by the presence of neonatal and foetal myosin, will be calculated from biopsies. Serum samples will be analysed to quantify the levels of specific microRNAs (miRs) associated with fibre leakage and peptide markers of active fibrosis which characterise fibre damage and degeneration respectively. We will present data from these candidate biomarkers tested in DMD, Becker and normal samples looking to demonstrate quantifiable changes which are indicative of benefit. In future clinical trials of utrophin modulators, and potentially other DMD therapeutic approaches, these biomarkers may be appropriate to confirm benefit to dystrophin deficient muscle.