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Splice switching therapies as personalised genetic treatments: Applications to muscular dystrophy, thalassemia and spinal muscular atrophy

Wilton, S. and Fletcher, S. (2009) Splice switching therapies as personalised genetic treatments: Applications to muscular dystrophy, thalassemia and spinal muscular atrophy. In: 6th Australasian Gene Therapy Society Meeting, 29 April - 1 May 2009, Kerry Packer Education Centre. Royal Prince Alfred Hospital, Sydney, NSW.


Protein-truncating mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD), the most common and severe form of childhood muscle wasting. The entire dystrophin protein is not necessary for near normal function, as some Becker muscular dystrophy patients with in-frame dystrophin gene deletions present with minor symptoms. A phosphorodiamidate morpholino oligomer designed to excise dystrophin exon 51 from the mature mRNA was evaluated in a Phase I clinical trial. The test compound was injected into the extensor digitorum brevis muscle of non-ambulant DMD patients, and subsequent analysis showed ‘‘an unequivocal, widespread and robust response in terms of dystrophin positive fibres’’. Systemic trials are now underway. This is good news for the estimated 10% of DMD individuals who may benefit from exon 51 skipping, what about other DMD mutations? While 10–12 AOs should restore the readingframe in the common genomic deletion hotspots, scores of AOs will be needed to by-pass the many different proteintruncating mutations spread across the gene. Multiple gene transcripts are generated from at least 75% of human genes through alternative splicing. Although this greatly increases our genetic plasticity, the additional levels of splicing control offer multiple opportunities for things to go wrong. An estimated 15% of all gene mutations induce abnormal pre-mRNA splicing. Splice switching AOs were first shown to suppress abnormal splicing by masking of activated cryptic splice sites that otherwise lead to aberrant mRNA, such as β-globin mutations causing thalassemia. In addition to inducing exon skipping or suppressing cryptic splice sites, some situations require an exon to be incorporated in the mature gene transcript. AO targeting of silencing elements in a pre-mRNA can promote exon inclusion, a mechanism relevant to the second most common autosomal recessive disorder, Spinal muscular atrophy. If exon skipping can be successfully applied to DMD, great opportunities lie ahead for splice switching therapies for other different genetic or acquired disorders.

Item Type: Conference Item
Notes: Keynote presentation
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