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A6 RNA targeted therapies – the experience from SMA and Duchenne’s muscular dystrophy
  1. Francesco Muntoni
  1. Dubowitz Neuromuscular Centre, Institute of Child Health and MRC Neuromuscular Centre, University College London and Great Ormond Street Hospital for Children, London, UK


Antisense oligonucleotides (AON) are increasingly used in neuromuscular and neurodegenerative disorders to either induce splice switching or for targeting and downregulating mutant mRNA. Two examples of splice switching use of AONs in neuromuscular disorders are Duchenne muscular dystrophy (DMD) in which AON are used to induce a skipping (i.e. exclusion) of an exon, while in spinal muscular atrophy (SMA), AONs are used to induce an exon retention.

In DMD, several hundreds of children with deletions eligible to skipping of exons 44; or 45; or 51 or 53 have been studied in phase I, II and III studies. Two main chemistries have been used, the 2’O Methyl (2’OMe) AON backbone; and the phosphorodiamidate morpholino (PMO) AON backbone. Both backbones have been quite extensively studied before in relevant animal models such as the mdx mouse and, the PMO, also in the more severe dystrophic dog models with encouraging results. These preclinical promising results have been paralleled by similarly encouraging results of the phase I and II studies of both chemistries. More recently however the failure of a phase III study for a 2’OMe AON targeting exon 51 and some safety concerns regarding the chronic systemic delivery of a 2’Ome AON led to discontinuation of the program in which these AON are being used, while the PMO program of research continues.

In SMA, the intratechal administration of a methoxy-ethyl (MOE) AON to induce retention of SMN2 exon 7 has very rapidly advanced from phase I to phase III studies. Both children with the severe SMA 1 variant (Werdnig Hoffman disease) and milder non ambulant children with SMA II and III (Kugelberg Welander disease) have now been treated. While the randomised, placebo controlled studies are still ongoing, the outcome of the earlier open label phase I and II studies is so far very encouraging both in terms of the safety and the exploratory efficacy of the study drug.

In my presentation, I will discuss the most recent results related to these studies both in DMD and SMA.

  • Antisense oligonucleotides
  • splice switching
  • Duchenne muscular dystrophy
  • Spinal muscular atrophy

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