Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies.

Abstract

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.

• Authors: Patricia Soblechero-Martín, Andrea López-Martínez, Laura de la Puente-Ovejero, Ainara Vallejo-Illarramendi, Virginia Arechavala-Gomeza
• Journal: Neuropathology and applied neurobiology (Neuropathol Appl Neurobiol) Vol. 47 Issue 6 Pg. 711-723 (10 2021) ISSN: 1365-2990 [Electronic] England
• PMID: 33999469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Chemical References

• Pharmaceutical Preparations
• Utrophin

Topics

• Animals
• Biopsy (methods)
• Disease Models, Animal
• Humans
• Muscle, Skeletal (drug effects, pathology)
• Muscular Dystrophy, Duchenne (drug therapy, genetics, metabolism)
• Pharmaceutical Preparations (metabolism)
• Utrophin (metabolism, therapeutic use)