Development of Utrophin Site Blocking Oligos (SBOs) to Treat Duchenne Muscular Dystrophy (DMD)

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Duchenne Muscular Dystrophy (DMD) is a common, fatal, genetic disease estimated to affect 1 in 3500 live- born males. Currently no definitive therapy exists for DMD providing the impetus for urgently developing therapies to address this unmet need. DMD is caused by mutations in the DMD gene leading to an absence of the dystrophin protein. Utrophin (dystrophin-related protein/DRP) is the autosomal homolog of dystrophin sharing extensive sequence similarity and organizational motifs with dystrophin. Utrophin up-regulation can functionally substitute for the missing dystrophin and ameliorate the dystrophic phenotype of the mdx animal model of DMD, providing biological validation of this approach. We and others have shown that important post-transcriptional mechanisms exist that decrease or repress utrophin expression in myofibres, in particular via binding of miRNAs (e.g. miR let-7c) to the 3' untranslated region (UTR) of utrophin. In a series of exciting translational studies, we have demonstrated that blocking miR let-7c mediated interaction with the 3’ UTR of utrophin, using different chemical classes of site blocking oligonucleotides (SBOs), is sufficient to ‘repress the repression’, increase utrophin expression, and rescue the dystrophic phenotype, in vivo. Importantly, our Proof of Concept (POC) for this strategy was obtained using a phosphorodiamidate morpholino oligonucleotide (PMO)-based SBO which has 100% sequence homology to the human utrophin gene, and hence is ideally suited for translational development. In this BPN proposal responding to PAR 21-163, we propose to develop SBO-based utrophin upregulators that are appropriate for entry into clinical trials as a novel therapeutic strategy for DMD.