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Recent Advances and Clinical Applications of Exon Inclusion for Spinal Muscular Atrophy

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Exon Skipping and Inclusion Therapies

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1828))

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in SMN1 that stops production of SMN (survival of motor neuron) protein. Insufficient levels of SMN results in the loss of motor neurons, which causes muscle weakness, respiratory distress, and paralysis. A nearly identical gene (SMN2) contains a C-to-T transition which excludes exon 7 from 90% of the mature mRNA transcripts, leading to unstable proteins which are targeted for degradation. Although SMN2 cannot fully compensate for a loss of SMN1 due to only 10% functional mRNA produced, the discovery of the intronic splicing silencer (ISS-N1) opened a doorway for therapy. By blocking its function with antisense oligonucleotides manipulated for high specificity and efficiency, exon 7 can be included to produce full-length mRNA, which then compensates for the loss of SMN1. Nusinersen (Spinraza), the first FDA-approved antisense oligonucleotide drug targeting SMA, was designed based on this concept and clinical studies have demonstrated a dramatic improvement in patients. Novel chemistries including phosphorodiamidate morpholino oligomers (PMOs) and locked nucleic acids (LNAs), as well as peptide conjugates such as Pip that facilitate accurate targeting to the central nervous system, are explored to increase the efficiency of exon 7 inclusion in the appropriate tissues to ameliorate the SMA phenotype. Due to the rapid advancement of treatments for SMA following the discovery of ISS-N1, the future of SMA treatment is highly promising.

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Acknowledgments

This work was supported by the University of Alberta Faculty of Medicine and Dentistry, Slipchuk SMA Research Foundation Research Grant, the Canadian Institutes of Health Research (CIHR), the Friends of Garrett Cumming Research Funds, HM Toupin Neurological Science Research Funds, the Muscular Dystrophy Canada, the Canada Foundation for Innovation, Alberta Enterprise and Advanced Education, and the Women and Children’s Health Research Institute (WCHRI).

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Authors and Affiliations

  1. Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Hae-Won Son & Toshifumi Yokota

  2. The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, Edmonton, AB, Canada

    Toshifumi Yokota

Authors
  1. Hae-Won Son
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  2. Toshifumi Yokota
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Correspondence to Toshifumi Yokota .

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Editors and Affiliations

  1. Medical Genetics, University of Alberta, Edmonton, AB, Canada

    Toshifumi Yokota

  2. Medical Genetics, University of Alberta, Edmonton, AB, Canada

    Rika Maruyama

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Son, HW., Yokota, T. (2018). Recent Advances and Clinical Applications of Exon Inclusion for Spinal Muscular Atrophy. In: Yokota, T., Maruyama, R. (eds) Exon Skipping and Inclusion Therapies. Methods in Molecular Biology, vol 1828. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8651-4_3

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  • DOI: https://doi.org/10.1007/978-1-4939-8651-4_3

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8650-7

  • Online ISBN: 978-1-4939-8651-4

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