Antisense oligonucleotide induced exon skipping as a treatment for Duchenne Muscular Dystrophy

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Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to dystrophin gene replacement therapies, due to the nature of the target (muscle fibres) and the size and complexity of the gene. This project will investigate an alternative genetic approach in cells expressing dystrophin (this gene is transcribed and processed differently in a variety cell types), whereby antisense oligonucleotides are used to redirect the processing of dystrophin pre-mRNA in the region of the DMD mutation. Although the DMD mutation would still be present at the gene level, the disease-causing mutation would be removed during the processing of the dystrophin pre-mRNA. Once a nonsense mutation has been removed or the reading frame restored from a DMD transcript, the resultant engineered dystrophin mRNA could be translated into a functional Becker-like protein.