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T.I.4 Splice manipulation therapies: Opportunities and challenges

Wilton, S. and Fletcher, S. (2008) T.I.4 Splice manipulation therapies: Opportunities and challenges. Neuromuscular Disorders, 18 (9-10). p. 831.

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A variety of oligomer chemistries allow gene expression to be modified via several distinct mechanisms: specific degradation through RNaseH action or gene silencing, translation blockade or redirection of splicing patterns, including exon excision or inclusion. Protein truncating mutations in the huge dystrophin gene typically lead to the most common and serious form of childhood muscle wasting, Duchenne muscular dystrophy (DMD). Exon skipping strategies can be developed to by-pass most DMD-causing mutations in the dystrophin gene transcript, in essence a form of molecular by-pass surgery allowing production of a protein of potentially near normal function. The distribution and complexity of dystrophin gene expression that posed great challenges for gene repair or replacement, may be regarded as positive attributes for induced exon skipping. Clinical trials are currently underway to assess some safety aspects, while addressing one of the most common sub-types of deletion mutation. These trials will provide proof-of-principle for targeted exon skipping in human skeletal muscle, an essential pre-requisite for subsequent systemic applications. Many different oligomers have been optimised in vitro, in preparation for subsequent application to different dystrophin mutations, once efficacy has been demonstrated by exon 51 skipping. Should dystrophin exon skipping prove to be beneficial in reducing the severity and progression of DMD, these studies may provide a useful platform to launch splice-intervention therapies for many different neuromuscular conditions, including suppression of abnormal splicing, enhancing exon 7 inclusion in the SMN2 gene transcript for SMA Type 1, and correction of abnormal splicing events in Myotonic Dystrophy Type 1.

Item Type: Journal Article
Publisher: Elsevier BV
Copyright: © 2008 Published by Elsevier B.V.
Notes: Abstract: 13th International Congress of the World Muscle Society, Newcastle Upon Tyne, UK. 29 September - 2 October 2008
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