dc.contributor
Institut Català de la Salut
dc.contributor
[Kagiava A, Karaiskos C, Lapathitis G, Sargiannidou I] Neuroscience Department, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. [Heslegrave A] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. UK Dementia Research Institute at UCL, London, UK. [Zetterberg H] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. UK Dementia Research Institute at UCL, London, UK. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, USA. [Bosch A] Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. Unitat Mixta UAB-VHIR, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
dc.contributor
Vall d'Hebron Barcelona Hospital Campus
dc.contributor.author
Kagiava, Alexia
dc.contributor.author
Karaiskos, Christos
dc.contributor.author
Lapathitis, George
dc.contributor.author
Heslegrave, Amanda
dc.contributor.author
Sargiannidou, Irene
dc.contributor.author
Zetterberg, Henrik
dc.contributor.author
Bosch, Assumpció
dc.date.accessioned
2025-10-24T08:55:45Z
dc.date.available
2025-10-24T08:55:45Z
dc.date.issued
2023-09-01T12:46:31Z
dc.date.issued
2023-09-01T12:46:31Z
dc.date.issued
2023-09-14
dc.identifier
Kagiava A, Karaiskos C, Lapathitis G, Heslegrave A, Sargiannidou I, Zetterberg H, et al. Gene replacement therapy in two Golgi-retained CMT1X mutants before and after the onset of demyelinating neuropathy. Mol Ther Methods Clin Dev. 2023 Sep 14;30:377–93.
dc.identifier
https://hdl.handle.net/11351/10214
dc.identifier
10.1016/j.omtm.2023.07.011
dc.identifier.uri
http://hdl.handle.net/11351/10214
dc.description.abstract
Golgi-retained mutations; Demyelination; Gene therapy
dc.description.abstract
Mutacions retingudes per Golgi; Desmielinització; Teràpia de genes
dc.description.abstract
Mutaciones retenidas por Golgi; Desmielinización; Terapia de genes
dc.description.abstract
X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) is a demyelinating neuropathy resulting from loss-of-function mutations affecting the GJB1/connexin 32 (Cx32) gene. We previously showed functional and morphological improvement in Gjb1-null mice following AAV9-mediated delivery of human Cx32 driven by the myelin protein zero (Mpz) promoter in Schwann cells. However, CMT1X mutants may interfere with virally delivered wild-type (WT) Cx32. To confirm the efficacy of this vector also in the presence of CMT1X mutants, we delivered AAV9-Mpz-GJB1 by lumbar intrathecal injection in R75W/Gjb1-null and N175D/Gjb1-null transgenic lines expressing Golgi-retained mutations, before and after the onset of the neuropathy. Widespread expression of virally delivered Cx32 was demonstrated in both genotypes. Re-establishment of WT Cx32 function resulted in improved muscle strength and increased sciatic nerve motor conduction velocities in all treated groups from both mutant lines when treated before as well as after the onset of the neuropathy. Furthermore, morphological analysis showed improvement of myelination and reduction of inflammation in lumbar motor roots and peripheral nerves. In conclusion, this study provides proof of principle for a clinically translatable gene therapy approach to treat CMT1X before and after the onset of the neuropathy, even in the presence of endogenously expressed Golgi-retained Cx32 mutants.
dc.description.abstract
This work was funded by the Muscular Dystrophy Association (MDA) and Charcot-Marie-Tooth Association (CMTA) (grant MDA 603003 to K.A.K.), as well as the UK Dementia Research Institute at UCL (UKDRI-1003 to H.Z. and A.H.).
dc.format
application/pdf
dc.format
application/pdf
dc.relation
Molecular Therapy - Methods & Clinical Development;30
dc.relation
https://doi.org/10.1016/j.omtm.2023.07.011
dc.rights
Attribution-NonCommercial-NoDerivatives 4.0 International
dc.rights
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights
info:eu-repo/semantics/openAccess
dc.subject
Teràpia genètica
dc.subject
Anomalies cromosòmiques
dc.subject
Neuropatia - Tractament
dc.subject
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation
dc.subject
DISEASES::Nervous System Diseases::Nervous System Malformations::Hereditary Sensory and Motor Neuropathy::Charcot-Marie-Tooth Disease
dc.subject
ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Biological Therapy::Genetic Therapy
dc.subject
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
dc.subject
ENFERMEDADES::enfermedades del sistema nervioso::malformaciones del sistema nervioso::neuropatía sensitiva y motora hereditaria::enfermedad de Charcot-Marie-Tooth
dc.subject
TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapia biológica::terapia genética
dc.title
Gene replacement therapy in two Golgi-retained CMT1X mutants before and after the onset of demyelinating neuropathy
dc.type
info:eu-repo/semantics/article
dc.type
info:eu-repo/semantics/publishedVersion
