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Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology

Nature Medicine volume 12, pages 175–177 (2006)Cite this article

A Correspondence to this article was published on 01 December 2006

Abstract

For the majority of Duchenne muscular dystrophy (DMD) mutations, antisense oligonucleotide (AON)-mediated exon skipping has the potential to restore a functional protein. Here we show that weekly intravenous injections of morpholino phosphorodiamidate (morpholino) AONs induce expression of functional levels of dystrophin in body-wide skeletal muscles of the dystrophic mdx mouse, with resulting improvement in muscle function. Although the level of dystrophin expression achieved varies considerably between muscles, antisense therapy may provide a realistic hope for the treatment of a majority of individuals with DMD.

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Figure 1: Induction of dystrophin expression in muscles from mdx mice with intravenous injection of morpholino AONs.
Figure 2: Immunohistochemistry and western blot analysis showing induction of dystrophin expression.

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Acknowledgements

This work was supported by Parent Project, UK Muscular Dystrophy; aktion benni & co e. V., Germany; Medical Research Council UK and Limb Girdle Muscular Dystrophy Fund, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, North Carolina, USA; Muscular Dystrophy Association, USA. Thanks also go to R.C. Woledge, Institute of Human Performance, University College London, UK; and A. Wilson, Structure and Motion Laboratory, Royal Veterinary College, London, UK, for providing equipment for part of the muscle contraction tests; R. Hemendinger, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, North Carolina, USA, for critical reading and comments. T.P. is recipient of a Chaire Internationale de Recherche Blaise Pascal de l'Etat de la Region d'Ile de France, Fondation de l'Ecole Normale Superieure.

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Authors and Affiliations

  1. Muscle Cell Biology, MRC Clinical Science Centre, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Julia Alter, Adam Rabinowitz, HaiFang Yin & Terence A Partridge

  2. School of Life Science, University of Hertfordshire, College Lane, Hatfield, AL10 9AB, Herts, UK

    Fang Lou

  3. Muscular Dystrophy Laboratory, Neuromuscular/ALS Center, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, 28231, North Carolina, USA

    Jeffrey Rosenfeld & Qi Long Lu

  4. Australian Neuromuscular Research Institute, Centre for Neuromuscular and Neurological Disorders, QEII Medical Centre University of Western Australia, Nedlands, 6009, Western Australia

    Steve D Wilton

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  1. Julia Alter
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  2. Fang Lou
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  3. Adam Rabinowitz
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  4. HaiFang Yin
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  7. Terence A Partridge
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Correspondence to Qi Long Lu.

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Supplementary information

Supplementary Fig. 1

Illustration of exon 23 skipping with morpholinos in the mdx mouse. (PDF 124 kb)

Supplementary Fig. 2

Immunohistochemistry of dystrophin expression in tibialis anterior (TA) muscles 2 weeks after single intramuscular injection of the morpholinos. (PDF 4094 kb)

Supplementary Fig. 3

Systemic delivery of morpholino antisense oligonucleotide restores dystrophin expression bodywide to functional levels and improves dystrophic pathology. (PDF 1508 kb)

Supplementary Fig. 4

Significant reduction in percentage of centrally nucleated muscle fibers is observed in the muscles from mdx mice treated with morpholino AONs (seven intravenous injections, white bars) when compared to the muscles from control mdx (black bars). (PDF 208 kb)

Supplementary Methods (PDF 33 kb)

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Alter, J., Lou, F., Rabinowitz, A. et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 12, 175–177 (2006). https://doi.org/10.1038/nm1345

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