Duchenne muscular dystrophy (DMD) is a devastating, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches (e.g. stop codon readthrough, exon skipping, gene therapy) are progressing through human clinical trials. By pharmacologically modulating the dystrophin-related protein utrophin, we aim to develop a therapy applicable to all DMD patients, regardless of the underlying genetic fault in the dystrophin gene, by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit Therapeutics, we previously developed SMT C1100, an oral small molecule utrophin modulator that reduces dystrophic symptoms in the mdxmouse and successfully completed a Phase 1b trial with an excellent safety profile in DMD patients.
The successful progression of SMT C1100 to date provides validation for the strategy we developed. We are now optimising second and third generations utrophin modulators with improved physicochemical properties and a more robust metabolism profile. Pre-clinical in vivo studies in the mdx mouse demonstrate that daily oral administration of these compounds increases utrophin expression in target muscle groups, including the diaphragm and heart. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis with no change in fibre type composition. These improvements combine to provide functional enhancement and protection of muscle from contraction induced damage. The use of small molecules to increase utrophin expression in skeletal, respiratory and cardiac muscles emphasises the potential of utrophin modulation as a disease-modifying therapeutic strategy for all DMD patients, irrespective of their mutation in dystrophin.