Implementation of splice switching therapies for duchenne muscular dystrophy
The exquisitely precise and co-ordinated process of gene transcript splicing, that is, intron removal and joining of exons, not only greatly increases genetic plasticity through alternative splicing, but also offers a point of therapeutic intervention for some genetic disorders. Protein truncating mutations in the 2.4Mbp, 79 exon dystrophin gene lead to Duchenne muscular dystrophy (DMD), the most common and severe form of childhood muscle wasting. The size and complexity of the dystrophin gene poses major challenges to gene replacement therapy for DMD, but antisense oligomer induced exon skipping has progressed from a concept demonstrated in vitro to clinical trials in just over a decade. Proof-of-concept was demonstrated by restoration of localised dystrophin synthesis after injection of a morpholino oligomer, designed to excise exon 51 from the dystrophin mRNA, into the extensior digitorum brevis of non-ambulant DMD patients with a common genomic deletion sub-type. Preliminary results from a systemic antisense oligomer, dose- escalating study over 12 weeks indicate that the compound is well- tolerated and showed that dystrophin synthesis was restored in patient muscle. Specific skipping of dystrophin exon 51 will only be relevant to about 10% of DMD individuals, however, we have developed a panel of oligomers to skip different dystrophin exons and allow treatment for other dystrophin mutations as a form of personalized genetic therapy. We now report that subtle DNA changes in the target exon influence the exon skipping efficiency of splice switching oligomers, further emphasizing the individual nature of this potential treatment. DMD is regarded as an orphan disease, and additional stratification of patients according to the nature of their primary gene lesion will pose great challenges to the application of this therapy.
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