Utrophin in the Therapy of Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) is caused by mutations that abolish the expression of the large cytoskeletal protein, dystrophin. DMD patients are usually wheelchair bound by the age of twelve years and die in their late teens or early twenties. There is currently no effective treatment. Utrophin is the autosomal homologue of dystrophin, sharing similar functional domains and protein binding partners, such that we hypothesised that utrophin may be able to replace dystrophin in DMD. Transgenic mdx mice expressing utrophin under the control of a human skeletal actin promoter have shown that utrophin can prevent the pathology in mdx mice and that this occurs if utrophin is administered at birth. Even in later stages of the disease, utrophin can have some therapeutic effect. One way to increase utrophin expression in muscle is transcriptional up-regulation of the endogenous gene. This would have the inherent attraction that problems surrounding delivery of therapeutic genes to muscle would be circumvented. We have undertaken a systematic investigation of the transcriptional regulation of the utrophin gene. Expression of utrophin is determined by two independently regulated promoters that are associated with unique first exons encoding different N-terminal isoforms. We have also shown that utrophin expression is fibre type dependent that may be mediated through NFAT motifs at the 5’end of promoter A. We have screened both promoters against small compound libraries and identified molecules that not only increase utrophin levels in muscle cell lines but also up-regulate utrophin in vivo in the mdx mouse. These compounds are currently being optimised for entry into preclinical studies.