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Development of LNA Gapmer Oligonucleotide-Based Therapy for ALS/FTD Caused by the C9orf72 Repeat Expansion

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Gapmers

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2176))

Abstract

Several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), have a complex genetic background, in addition to cases where the disease appears to manifest sporadically. The recent discovery of the hexanucleotide repeat expansion in the C9orf72 gene as the causative agent of ALS (C9ALS) gives rise to the opportunity to develop new therapies directed at this mutation , which is responsible for a large proportion of ALS and/or frontotemporal dementia cases. Mammalian models conscientiously replicating the late-onset motor defects and cellular pathologies seen in human patients do not exist. In this context, patient-derived cells give us a platform to test potential antisense oligonucleotide therapies, which could be the key to treat this subtype of motor neuron disease. Recently, we described that locked nucleic acid gapmer oligonucleotide-based treatment targeting C9orf72 repeat expanded transcripts resulted in recovery from the disease-related phenotypes in patient-derived fibroblasts. Our findings highlight the therapeutic potential of C9ALS using this gapmer oligonucleotide-based approach.

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Acknowledgments

This work was supported by a Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (C) [grant number 18 K11067 to N.M and 18 K07544 to Y.A.], Grants-in-Aid for Research on Nervous and Mental Disorders [grant number 28-6 to Y.A.], and the Japan Agency for Medical Research and Development [grant numbers 19ek0109239h0003 and 19lm0203086h0001 to Y.A.].

Author information

Authors and Affiliations

  1. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Chaitra Sathyaprakash & Kevin Talbot

  2. Department of Paediatrics, Anatomy and Genetics, University of Oxford, Oxford, UK

    Raquel Manzano, Miguel A. Varela & Matthew J. A. Wood

  3. Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan

    Yasumasa Hashimoto & Yoshitsugu Aoki

Authors
  1. Chaitra Sathyaprakash
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  2. Raquel Manzano
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  3. Miguel A. Varela
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  4. Yasumasa Hashimoto
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  5. Matthew J. A. Wood
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  6. Kevin Talbot
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  7. Yoshitsugu Aoki
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Corresponding author

Correspondence to Yoshitsugu Aoki .

Editor information

Editors and Affiliations

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

    Toshifumi Yokota

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

    Rika Maruyama

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Sathyaprakash, C. et al. (2020). Development of LNA Gapmer Oligonucleotide-Based Therapy for ALS/FTD Caused by the C9orf72 Repeat Expansion. In: Yokota, T., Maruyama, R. (eds) Gapmers. Methods in Molecular Biology, vol 2176. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0771-8_14

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  • DOI: https://doi.org/10.1007/978-1-0716-0771-8_14

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0770-1

  • Online ISBN: 978-1-0716-0771-8

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