Antisense mediated exon selection to alter gene expression in the study of Disease

S. Fletcher

Duchenne muscular dystrophy (DMD) is an X-linked, relentlessly progressive muscle wasting disorder, caused by mutations in the DMD gene that compromise function of dystrophin, a sub sarcolemmal protein. DMD has a predictable course and limited treatment options, with the majority of cases being caused by frame-shifting deletions of one or more of the 79 exons of DMD. Deletions that do not disrupt the dystrophin open reading frame generally cause the milder allelic disorder, Becker muscular dystrophy (BMD). Antisense oligomer (AO)-mediated splicing manipulation can remove specific exons during transcript processing to reframe the transcript and overcome DMD-causing dystrophin gene lesions to generate shorter, partially functional dystrophin isoforms, and is showing promise as a therapy for DMD. Dystrophin gene structure in patients with mild phenotypes can provide templates for potentially functional dystrophin isoforms. However, such mutations downstream of exon 55 are rare, and the probable consequences of AO-induced exon removal in this region are not known. We report that systemic administration of antisense phosphorodiamidate morpholino oligomer-cell penetrating peptide conjugates to wild-type C57BL/10ScSn mice can remove dystrophin exons to generate in vivo dystrophic models for molecular, physiological and pathology evaluation. Exclusion of selected exons within the beta dystroglycan and syntrophin binding domains is elucidating the relative importance of these regions to dystrophin function, and may provide guidelines for the development of therapeutic exon skipping strategies.

Antisense mediated exon selection to alter gene expression in the study of Disease

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