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Utrophin modulators significantly improve muscular dystrophy in the mdx diaphragm

      Duchenne muscular dystrophy (DMD) is a severe muscle degenerative disease caused by genetic mutation in the dystrophin gene resulting in the loss of dystrophin function. Affected individuals succumb to heart or respiratory failure by 30 years of age. Currently, there is no effective treatment for DMD although a number of disease-modifying drugs are progressing in clinical trials. We have previously demonstrated that the dystrophin-related protein utrophin, a structural and functional autosomal paralogue of dystrophin, can act as an effective surrogate to compensate for the loss of dystrophin in mdx muscle. By using oral small molecules specially designed to target the muscle-specific utrophin-A promoter, we aim to develop a treatment for all DMD patients irrespective of their dystrophin mutation. In partnership with Summit Therapeutics, we previously developed SMT C1100, an oral utrophin modulator that reduces dystrophic symptoms in the mdx mouse and successfully completed a Phase 1b trial with an excellent safety profile in DMD patients. We are now conducting studies in the mdx mouse with second generation utrophin modulators with improved physicochemical properties and a more robust metabolism profile. Unlike skeletal and cardiac muscles, the mdx diaphragm exhibits a highly dystrophic pathology and closely mimics the degeneration and necrosis observed in DMD patients. The diaphragm is the most reliable indicator of damage or recovery and therefore the more stringent preclinical test to demonstrate potential therapy. Thus, by using histological and molecular methods, we evaluated and compared the benefits of second generation utrophin modulators in the mdx diaphragm. The results of these evaluations will be presented and their relevance to potential clinical development discussed.
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