AAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1 A

Benoit Gautier (), Helene Hajjar, Sylvia Soares, Jade Berthelot, Marie Deck, Scarlette Abbou, Graham Campbell, Maria Ceprian, Sergio Gonzalez, Claire-Maëlle Fovet, Vlad Schütza, Antoine Jouvenel, Cyril Rivat, Michel Zerah, Virginie François, Caroline Guiner, Patrick Aubourg, Robert Fledrich () and Nicolas Tricaud ()
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Benoit Gautier: INM, Univ. Montpellier, INSERM
Helene Hajjar: INM, Univ. Montpellier, INSERM
Sylvia Soares: Sorbonne Université, CNRS, INSERM, IBPS, Neuroscience Paris Seine
Jade Berthelot: INM, Univ. Montpellier, INSERM
Marie Deck: INM, Univ. Montpellier, INSERM
Scarlette Abbou: INM, Univ. Montpellier, INSERM
Graham Campbell: INM, Univ. Montpellier, INSERM
Maria Ceprian: INM, Univ. Montpellier, INSERM
Sergio Gonzalez: INM, Univ. Montpellier, INSERM
Claire-Maëlle Fovet: INSERM U1184, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, CEA
Vlad Schütza: Institute of Anatomy, Leipzig University
Antoine Jouvenel: INM, Univ. Montpellier, INSERM
Cyril Rivat: INM, Univ. Montpellier, INSERM
Michel Zerah: Paediatric Neurosurgery Department, Université Paris Descartes and Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Necker
Virginie François: INSERM UMR 1089, Université de Nantes, CHU de Nantes
Caroline Guiner: INSERM UMR 1089, Université de Nantes, CHU de Nantes
Patrick Aubourg: Centre Hospitalier Universitaire de Bicêtre
Robert Fledrich: Institute of Anatomy, Leipzig University
Nicolas Tricaud: INM, Univ. Montpellier, INSERM

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Charcot-Marie-Tooth disease 1 A (CMT1A) results from a duplication of the PMP22 gene in Schwann cells and a deficit of myelination in peripheral nerves. Patients with CMT1A have reduced nerve conduction velocity, muscle wasting, hand and foot deformations and foot drop walking. Here, we evaluate the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9) expressing GFP and shRNAs targeting Pmp22 mRNA in animal models of Charcot-Marie-Tooth disease 1 A. Intra-nerve delivery of AAV2/9 in the sciatic nerve allowed widespread transgene expression in resident myelinating Schwann cells in mice, rats and non-human primates. A bilateral treatment restore expression levels of PMP22 comparable to wild-type conditions, resulting in increased myelination and prevention of motor and sensory impairments over a twelve-months period in a rat model of CMT1A. We observed limited off-target transduction and immune response using the intra-nerve delivery route. A combination of previously characterized human skin biomarkers is able to discriminate between treated and untreated animals, indicating their potential use as part of outcome measures.

Date: 2021
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DOI: 10.1038/s41467-021-22593-3

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