ArticleCommunications medicine2023
AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells.
Article in Communications medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 6 citations in OpenAlex.
- Identification and Targeted Correction of a PathogenicInternational journal of molecular sciences · 2026Article
- The current status of Charcot-Marie-Tooth disease type 1 A treatment.Acta neurologica Belgica · 2025Review
- Emerging Approaches to Mitigate Neural Cell Degeneration with Nanoparticles-Enhanced Polyelectrolyte Systems.Membranes · 2025Review
- Pathologic and Therapeutic Schwann Cells.Cells · 2025Review
- Photocleavable Guide crRNAs for a Light-Controllable CRISPR/Cas9 System.International journal of molecular sciences · 2024Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundCharcot-Marie-Tooth disease type 1A (CMT1A) is one of the most common hereditary peripheral neuropathies caused by duplication of 1.5 Mb genome region including PMP22 gene. We aimed to correct the duplication in human CMT1A patient-derived iPS cells (CMT1A-iPSCs) by genome editing and intended to analyze the effect on Schwann cells differentiated from CMT1A-iPSCs.
methodsWe designed multiple gRNAs targeting a unique sequence present at two sites that sandwich only a single copy of duplicated peripheral myelin protein 22 (PMP22) genes, and selected one of them (gRNA3) from screening their efficiencies by T7E1 mismatch detection assay. AAV2-hSaCas9-gRNAedit was generated by subcloning gRNA3 into pX601-AAV-CMV plasmid, and the genome editing AAV vector was infected to CMT1A-iPSCs or CMT1A-iPSC-derived Schwann cell precursors. The effect of the genome editing AAV vector on myelination was evaluated by co-immunostaining of myelin basic protein (MBP), a marker of mature myelin, and microtubule-associated protein 2(MAP2), a marker of neurites or by electron microscopy.
resultsHere we show that infection of CMT1A-iPS cells (iPSCs) with AAV2-hSaCas9-gRNAedit expressing both hSaCas9 and gRNA targeting the tandem repeat sequence decreased PMP22 gene duplication by 20-40%. Infection of CMT1A-iPSC-derived Schwann cell precursors with AAV2-hSaCas9-gRNAedit normalized PMP22 mRNA and PMP22 protein expression levels, and also ameliorated increased apoptosis and impaired myelination in CMT1A-iPSC-derived Schwann cells.
conclusionsIn vivo transfer of AAV2-hSaCas9-gRNAedit to peripheral nerves could be a potential therapeutic modality for CMT1A patient after careful examinations of toxicity including off-target mutations.
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