Résumé :
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Modulation and variability in (i) exon splicing (exon skipping), and (ii) RNA stability and translation (RNA interference), are naturally occurring phenomena now being harnessed as therapeutic strategies to treat inherited diseases like the muscular dystrophies, and to enhance our understanding of the molecular bases of these conditions. In mice, dog and humans, antisense oligonucleotides (AONs) have been developed to skip exons causing frame-shifting and nonsense mutations in the dystrophin gene. Biologically active AONs result in ORF restoration in mRNAs, and truncated dystrophin expression, in treated muscle and individuals. The UK MDEX Consortium is evaluating morpholino antisense oligomers (PMOs) using intramuscular delivery in a Phase I clinical trial in DMD patients. Progress of this trial will be discussed along with examples of preclinical studies to optimise selection and administration of PMOs. In the context of therapeutic use of RNAi technology, studies will be described on knockdown of the poly(A) binding protein (PABPN1) gene which harbours the expanded trinucleotide (GCG) repeat mutation causing autosomal dominant oculopharyngeal muscular dystrophy (OPMD). In addition we will report on the outcome of in vivo RNAi knockdown of the dystrophin gene which has led to novel insights into the pathophysiology of DMD.
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