Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies.
Patricia Soblechero-MartínAndrea López-MartínezLaura de-la-Puente-OvejeroAinara Vallejo-IllarramendiVirginia Arechavala-GomezaPublished in: Neuropathology and applied neurobiology (2021)
Utrophin is an autosomal paralogue of dystrophin, a protein whose deficit causes Duchenne and Becker muscular dystrophies (DMD/BMD). Utrophin is naturally overexpressed at the sarcolemma of mature dystrophin-deficient fibres in DMD and BMD patients as well as in the mdx Duchenne mouse model. Dystrophin and utrophin can co-localise in human foetal muscle, in the dystrophin-competent fibres from DMD/BMD carriers, and revertant fibre clusters in biopsies from DMD patients. These findings suggest that utrophin overexpression could act as a surrogate, compensating for the lack of dystrophin, and, as such, it could be used in combination with dystrophin restoration therapies. Different strategies to overexpress utrophin are currently under investigation. In recent years, many compounds have been reported to modulate utrophin expression efficiently in preclinical studies and ameliorate the dystrophic phenotype in animal models of the disease. In this manuscript, we discuss the current knowledge on utrophin protein and the different mechanisms that modulate its expression in skeletal muscle. We also include a comprehensive review of compounds proposed as utrophin regulators and, as such, potential therapeutic candidates for these muscular dystrophies.
Keyphrases
- muscular dystrophy
- duchenne muscular dystrophy
- skeletal muscle
- end stage renal disease
- mouse model
- newly diagnosed
- ejection fraction
- poor prognosis
- chronic kidney disease
- endothelial cells
- binding protein
- peritoneal dialysis
- type diabetes
- metabolic syndrome
- cell proliferation
- mesenchymal stem cells
- ultrasound guided
- high intensity
- wild type