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

Autor: Gautier B; INM, Univ. Montpellier, INSERM, Montpellier, France. benoit.gautier@inserm.fr., Hajjar H; INM, Univ. Montpellier, INSERM, Montpellier, France.; Institute of Regenerative Medicine and Biotherapies (IRMB), University of Montpellier, INSERM, Montpellier, France., Soares S; Sorbonne Université, CNRS, INSERM, IBPS, Neuroscience Paris Seine, Paris, France., Berthelot J; INM, Univ. Montpellier, INSERM, Montpellier, France., Deck M; INM, Univ. Montpellier, INSERM, Montpellier, France., Abbou S; INM, Univ. Montpellier, INSERM, Montpellier, France., Campbell G; INM, Univ. Montpellier, INSERM, Montpellier, France., Ceprian M; INM, Univ. Montpellier, INSERM, Montpellier, France.; Laboratory of Pathogen-Host Interactions (LPHI), University of Montpellier, Montpellier, France., Gonzalez S; INM, Univ. Montpellier, INSERM, Montpellier, France.; Laboratory of Pathogen-Host Interactions (LPHI), University of Montpellier, Montpellier, France., Fovet CM; INSERM U1184, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, CEA, Fontenay-Aux-Roses, France., Schütza V; Institute of Anatomy, Leipzig University, Leipzig, Germany., Jouvenel A; INM, Univ. Montpellier, INSERM, Montpellier, France., Rivat C; INM, Univ. Montpellier, INSERM, Montpellier, France., Zerah M; Paediatric Neurosurgery Department, Université Paris Descartes and Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Necker, Paris, France., François V; INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France., Le Guiner C; INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France., Aubourg P; Department of Paediatric Neurology, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicètre, France.; INSERM U1169, Université Paris-Sud, Orsay, France., Fledrich R; Institute of Anatomy, Leipzig University, Leipzig, Germany. robert.fledrich@medizin.uni-leipzig.de., Tricaud N; INM, Univ. Montpellier, INSERM, Montpellier, France. nicolas.tricaud@inserm.fr.; I-Stem, UEVE/UPS U861, INSERM U861, AFM, Corbeil-Essonnes, France. nicolas.tricaud@inserm.fr.; Laboratory of Pathogen-Host Interactions (LPHI), University of Montpellier, Montpellier, France. nicolas.tricaud@inserm.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Apr 21; Vol. 12 (1), pp. 2356. Date of Electronic Publication: 2021 Apr 21.
DOI: 10.1038/s41467-021-22593-3
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: