Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons

Authors

  • Takenari Yamashita,

    1. CREST, Japan Science and Technology Agency, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    2. Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    3. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan
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  • Hui Lin Chai,

    1. CREST, Japan Science and Technology Agency, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    2. Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    3. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan
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  • Sayaka Teramoto,

    1. CREST, Japan Science and Technology Agency, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    2. Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    3. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan
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  • Shoji Tsuji,

    1. Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
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  • Kuniko Shimazaki,

    1. Department of Neurosurgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
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  • Shin-ichi Muramatsu,

    1. Department of Neurology, Jichi Medical University, Shimotsuke, Tochigi, Japan
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  • Shin Kwak

    Corresponding author
    1. CREST, Japan Science and Technology Agency, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    2. Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    3. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan
    4. Clinical Research Center for Medicine, International University of Health and Welfare, Ichikawa, Chiba, Japan
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Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and the lack of effective therapy results in inevitable death within a few years of onset. Failure of GluA2 RNA editing resulting from downregulation of the RNA-editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) occurs in the majority of ALS cases and causes the death of motor neurons via a Ca2+-permeable AMPA receptor-mediated mechanism. Here, we explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration. A single intravenous injection of AAV9-ADAR2 in conditional ADAR2 knockout mice (AR2), which comprise a mechanistic mouse model of sporadic ALS, caused expression of exogenous ADAR2 in the central neurons and effectively prevented progressive motor dysfunction. Notably, AAV9-ADAR2 rescued the motor neurons of AR2 mice from death by normalizing TDP-43 expression. This AAV9-mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.

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