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Development of Digital Tissue Image Analysis Solution for Muscle Biopsies in Support of Disease-Modifying Therapies for Duchenne Muscular Dystrophy

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Abstract:

The continual expression of utrophin protein by pharmacological maintenance of utrophin transcription in dystrophin-deficient muscle fibres is potentially a disease-modifying treatment for Duchenne muscular dystrophy (DMD) regardless of the specific dystrophin mutation. The evaluation of molecular biomarkers of muscle regeneration and structural protein complexes, such as developmental myosin and dystroglycans respectively, may be important endpoints in future clinical trials of utrophin modulators. Building on a recently published manual quantification approach, which demonstrated a positive correlation between utrophin levels and the degree of muscle fiber regeneration in DMD and Becker muscular dystrophy (BMD) muscle biopsies, the development of fully automated processes is ongoing.

Here, we report the development of multiplex immunohistochemical (IHC) assays and digital tissue image analysis (tIA) solutions for robustly quantifying utrophin, developmental myosin heavy chain, and beta-dystroglycan expression in DMD, BMD, and control muscle biopsies. The tIA approach enabled detection of biomarker signal features (e.g., cumulative intensities) and tissue morphometrics (e.g., ber area and minimum diameter) in whole-slide images of muscle cryosections at an individual muscle fiber resolution.

The tIA solutions reproducibly demonstrated quantifiable differences in levels of utrophin, and regeneration between DMD, BMD, and control biopsies. These biomarkers may be informative endpoints for evaluating pharmacologic bene t in dystrophin-deficient muscle in future clinical trials of utrophin modulators and potentially other DMD therapeutic approaches.

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