Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Share this article
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Abstract
  • Supplemental material
  • Version history
  • Article usage
  • Citations to this article

Advertisement

ResearchIn-Press PreviewNeuroscienceTherapeutics Open Access | 10.1172/JCI159814

A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

Marina Stavrou,1 Alexia Kagiava,1 Sarah G. Choudury,2 Matthew J. Jennings,3 Lindsay M. Wallace,2 Allison M. Fowler,2 Amanda Heslegrave,4 Jan Richter,5 Christina Tryfonos,5 Christina Christodoulou,5 Henrik Zetterberg,6 Rita Horvath,3 Scott Q. Harper,2 and Kleopas A. Kleopa1

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Stavrou, M. in: JCI | PubMed | Google Scholar |

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Kagiava, A. in: JCI | PubMed | Google Scholar |

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Choudury, S. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Jennings, M. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Wallace, L. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Fowler, A. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Heslegrave, A. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Richter, J. in: JCI | PubMed | Google Scholar |

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Tryfonos, C. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Christodoulou, C. in: JCI | PubMed | Google Scholar |

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Zetterberg, H. in: JCI | PubMed | Google Scholar |

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Horvath, R. in: JCI | PubMed | Google Scholar |

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Harper, S. in: JCI | PubMed | Google Scholar

1Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

2Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, United States of America

3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom

5Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

6Institute of Laboratory Medicine, Göteborgs University, Göteborg, Sweden

Find articles by Kleopa, K. in: JCI | PubMed | Google Scholar |

Published May 17, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI159814.
Copyright © 2022, Stavrou et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 17, 2022 - Version history
View PDF
Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using novel artificial microRNAs targeting human and mouse PMP22/Pmp22 mRNAs. Our lead therapeutic microRNA, miR871, was packaged into an AAV9 vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22/Pmp22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. Treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.

Supplemental material

View

Version history
  • Version 1 (May 17, 2022): In-Press Preview

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Share this article
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Abstract
  • Supplemental material
  • Version history
Advertisement
Advertisement

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts