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Citation: JNS Volume 187, Supplement 1, page S428, June 2001
K. Davies, K. Perkins, A. Weir, S. Squire, R. Fisher, J. Fernihough, S. Phelps, G. Harrod, K.E. Davies
University of Oxford, UK
DMD is caused by mutations that abolish expression of dystrophin. Utrophin is the autosomal homologue of dystrophin. The two proteins share similar functional domains and protein binding partners, such that we hypothesised that utrophin may be able to replace dystrophin in DMD. To address this question, transgenic mice expressing utrophin under the control of a human skeletal actin promoter were generated and bred onto the dystrophin-deficient mdx background. The morphological and physiological abnormalities characteristic of mdx mice were prevented, indicating that utrophin can replace dystrophin in this model. Furthermore, delivery of utrophin to mdx muscle using a recombinant adenovirus corrected muscle pathology in six week old dystrophin/utrophin null mutant mice, indicating that utrophin up-regulation is an effective mode of therapy after the clinical onset of disease in this model. One potential 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. To facilitate achieving this goal, 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. One of the promoters is synaptically regulated in muscle. We are currently screening both promoters against small compound libraries in order to identify molecules that may increase their activity in muscle.
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