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

Marina Stavrou; Alexia Kagiava; Sarah G. Choudury; Matthew J. Jennings; Lindsay M. Wallace; Allison M. Fowler; Amanda Heslegrave; Jan Richter; Christina Tryfonos; Christina Christodoulou; Henrik Zetterberg; Rita Horvath; Scott Q. Harper; Kleopas A. Kleopa

doi:10.1172/JCI159814

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 |

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

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.

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

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

Article tools

Metrics

Go to

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

Article tools

Metrics

Go to

Sign up for email alerts

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