Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an ultrarare, infantile-onset leukodystrophy characterized by white matter edema for which there is no treatment. More than 75% of diagnosed cases result from biallelic loss-offunction mutations in the astrocyte-specific gene MLC1,...

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Authors: Brao, Alejandro, Sánchez, Ángela, Rodríguez, Irina, Rey, Javier del, Lope Piedrafita, Silvia, Prat, Esther, Nunes Martínez, Virginia, Chillón, Miguel, Estévez Povedano, Raúl, Bosch, Assumpció
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/221916
Online Access:https://hdl.handle.net/2445/221916
Access Level:Open access
Keyword:Teràpia genètica
Edema cerebral
Cerebel
Gene therapy
Cerebral edema
Cerebellum
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spelling Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cystsBrao, AlejandroSánchez, ÁngelaRodríguez, IrinaRey, Javier delLope Piedrafita, SilviaPrat, EstherNunes Martínez, VirginiaChillón, MiguelEstévez Povedano, RaúlBosch, AssumpcióTeràpia genèticaEdema cerebralCerebelGene therapyCerebral edemaCerebellumMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is an ultrarare, infantile-onset leukodystrophy characterized by white matter edema for which there is no treatment. More than 75% of diagnosed cases result from biallelic loss-offunction mutations in the astrocyte-specific gene MLC1, leading to early-onset macrocephaly, cerebellar ataxia, epilepsy, and mild cognitive decline. To develop a gene therapy for MLC, we administered an adeno-associated viral vector capable of crossing the murine blood-brain barrier, delivering the human MLC1 cDNA under the control of a human astrocyte-specific promoter, to 10-month-old Mlc1-'- mice. We observed long-term astrocyte-driven expression of MLC1 up to 1 year after viral vector administration in all brain areas analyzed. Despite the late-stage intervention, in vivo magnetic resonance imaging revealed normalization of water accumulation. Notably, our therapy successfully reversed locomotor deficits in Mlc1-'- mice, as evidenced by improved performance in motor tests assessing cerebellar ataxia-like behaviors. Collectively, these findings not only demonstrate the sustained efficacy of our gene therapy but also highlight the reversibility of vacuolation and motor impairments in Mlc1-'- mice, suggesting that MLC patients could benefit from treatment even after symptom onset.Elsevier BV2025202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion15 p.application/pdfhttps://hdl.handle.net/2445/221916Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.ymthe.2025.02.046Molecular Therapy, 2025, vol. 33, num. 4, p. 1434-1448https://doi.org/10.1016/j.ymthe.2025.02.046cc by-nc-nd (c) Brao, Alejandro et al., 2025http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2219162026-05-29T05:05:01Z
dc.title.none.fl_str_mv Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
title Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
spellingShingle Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
Brao, Alejandro
Teràpia genètica
Edema cerebral
Cerebel
Gene therapy
Cerebral edema
Cerebellum
title_short Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
title_full Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
title_fullStr Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
title_full_unstemmed Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
title_sort Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
dc.creator.none.fl_str_mv Brao, Alejandro
Sánchez, Ángela
Rodríguez, Irina
Rey, Javier del
Lope Piedrafita, Silvia
Prat, Esther
Nunes Martínez, Virginia
Chillón, Miguel
Estévez Povedano, Raúl
Bosch, Assumpció
author Brao, Alejandro
author_facet Brao, Alejandro
Sánchez, Ángela
Rodríguez, Irina
Rey, Javier del
Lope Piedrafita, Silvia
Prat, Esther
Nunes Martínez, Virginia
Chillón, Miguel
Estévez Povedano, Raúl
Bosch, Assumpció
author_role author
author2 Sánchez, Ángela
Rodríguez, Irina
Rey, Javier del
Lope Piedrafita, Silvia
Prat, Esther
Nunes Martínez, Virginia
Chillón, Miguel
Estévez Povedano, Raúl
Bosch, Assumpció
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Teràpia genètica
Edema cerebral
Cerebel
Gene therapy
Cerebral edema
Cerebellum
topic Teràpia genètica
Edema cerebral
Cerebel
Gene therapy
Cerebral edema
Cerebellum
description Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an ultrarare, infantile-onset leukodystrophy characterized by white matter edema for which there is no treatment. More than 75% of diagnosed cases result from biallelic loss-offunction mutations in the astrocyte-specific gene MLC1, leading to early-onset macrocephaly, cerebellar ataxia, epilepsy, and mild cognitive decline. To develop a gene therapy for MLC, we administered an adeno-associated viral vector capable of crossing the murine blood-brain barrier, delivering the human MLC1 cDNA under the control of a human astrocyte-specific promoter, to 10-month-old Mlc1-'- mice. We observed long-term astrocyte-driven expression of MLC1 up to 1 year after viral vector administration in all brain areas analyzed. Despite the late-stage intervention, in vivo magnetic resonance imaging revealed normalization of water accumulation. Notably, our therapy successfully reversed locomotor deficits in Mlc1-'- mice, as evidenced by improved performance in motor tests assessing cerebellar ataxia-like behaviors. Collectively, these findings not only demonstrate the sustained efficacy of our gene therapy but also highlight the reversibility of vacuolation and motor impairments in Mlc1-'- mice, suggesting that MLC patients could benefit from treatment even after symptom onset.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/221916
url https://hdl.handle.net/2445/221916
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.ymthe.2025.02.046
Molecular Therapy, 2025, vol. 33, num. 4, p. 1434-1448
https://doi.org/10.1016/j.ymthe.2025.02.046
dc.rights.none.fl_str_mv cc by-nc-nd (c) Brao, Alejandro et al., 2025
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Brao, Alejandro et al., 2025
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 15 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869410233183371264
score 15.812429

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