Exon skipping therapies to address DMD-causing mutations targeting exon blocks
Forrest, S., Meloni, P., Fletcher, S. and Wilton, S. (2009) Exon skipping therapies to address DMD-causing mutations targeting exon blocks. In: 6th Australasian Gene Therapy Society Meeting, 29 April - 1 May 2009, Kerry Packer Education Centre. Royal Prince Alfred Hospital, Sydney, NSW.
Duchenne Muscular Dystrophy (DMD) is an X-linked disorder resulting in severe muscle wasting, beginning in the lower limbs and rapidly progressing to all voluntary muscles of the body. The disease is generally caused by protein truncating mutations in the dystrophin gene and results in the absence of a functional protein, known to provide a structural link between the muscle cytoskeleton and extra cellular matrix to maintain muscle integrity. Becker Muscular Dystrophy (BMD), a less severe form of muscular dystrophy, is generally caused by in-frame dystrophin exon deletions resulting in a shorter protein with variable functionality, depending upon the region and/or amount of the dystrophin gene lost. We have developed and optimised a series of antisense oligomers (AO’s) targeting the isolated removal of exons 2 to 78 of the 79 exon dystrophin gene, with the current focus upon the removal of in-frame exon blocks. Targeted removal of exon blocks would minimize the number of oligomer preparations required to address clustered dystrophin mutations and may facilitate establishment of dosage regimes. We report the targeted excision of dystrophin exons 17 and 18, with an oligomer cocktail to address three different mutations in this region. At the dystrophin transcript level, there appears to be variable responses to the oligomer cocktail, with the exon 18 duplication mutation being most amenable to splice intervention.
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