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ResearchIn-Press PreviewNeuroscienceTherapeutics
Open Access | 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
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Stavrou, M.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Horvath, R.
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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
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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
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Published May 17, 2022 - More info
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.