Gene therapy for Lafora disease in the Epm2a-/- mouse model
Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. The disease results from mutations in the EPM2A gene, encoding laforin, or the EPM2B gene, encoding malin. Laforin and malin work together in a complex to control glycogen synthesis an...
| Autores: | , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/396187 |
| Acceso en línea: | http://hdl.handle.net/10261/396187 https://api.elsevier.com/content/abstract/scopus_id/85196057293 |
| Access Level: | acceso abierto |
| Palabra clave: | Epm2a(−/−) knockout mouse Gene therapy Laforin polyglucosans Progressive myoclonic epilepsy rAAV http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages |
| id |
ES_f009b28f1ec1536ff30bd4dca59d96bf |
|---|---|
| oai_identifier_str |
oai:digital.csic.es:10261/396187 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| dc.title.none.fl_str_mv |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| title |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| spellingShingle |
Gene therapy for Lafora disease in the Epm2a-/- mouse model Zafra-Puerta, Luis Epm2a(−/−) knockout mouse Gene therapy Laforin polyglucosans Progressive myoclonic epilepsy rAAV http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages |
| title_short |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| title_full |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| title_fullStr |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| title_full_unstemmed |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| title_sort |
Gene therapy for Lafora disease in the Epm2a-/- mouse model |
| dc.creator.none.fl_str_mv |
Zafra-Puerta, Luis Iglesias-Cabeza, Nerea Burgos, Daniel F. Sciaccaluga, Miriam González-Fernández, Juan Bellingacci, Laura Canonichesi, Jacopo Sánchez-Martín, Gema Costa, Cinzia Sánchez, Marina P. Serratosa, José M. |
| author |
Zafra-Puerta, Luis |
| author_facet |
Zafra-Puerta, Luis Iglesias-Cabeza, Nerea Burgos, Daniel F. Sciaccaluga, Miriam González-Fernández, Juan Bellingacci, Laura Canonichesi, Jacopo Sánchez-Martín, Gema Costa, Cinzia Sánchez, Marina P. Serratosa, José M. |
| author_role |
author |
| author2 |
Iglesias-Cabeza, Nerea Burgos, Daniel F. Sciaccaluga, Miriam González-Fernández, Juan Bellingacci, Laura Canonichesi, Jacopo Sánchez-Martín, Gema Costa, Cinzia Sánchez, Marina P. Serratosa, José M. |
| author2_role |
author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Economía y Competitividad (España) Fundación Tatiana Pérez de Guzmán el Bueno Centro de Investigación Biomédica en Red Enfermedades Raras (España) BIRD Foundation National Institute of Neurological Disorders and Stroke (US) CSIC - Instituto de Biomedicina de Valencia (IBV) Hospital Universitario Fundación Jiménez Díaz Zafra-Puerta, Luis [0000-0002-1807-7538] Serratosa, José M. [0000-0003-2239-8948] Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Epm2a(−/−) knockout mouse Gene therapy Laforin polyglucosans Progressive myoclonic epilepsy rAAV http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages |
| topic |
Epm2a(−/−) knockout mouse Gene therapy Laforin polyglucosans Progressive myoclonic epilepsy rAAV http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages |
| description |
Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. The disease results from mutations in the EPM2A gene, encoding laforin, or the EPM2B gene, encoding malin. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein cause alterations in this complex, leading to the formation of Lafora bodies containing abnormal, insoluble, and hyperphosphorylated forms of glycogen. We used the Epm2a-/- knockout mouse model of Lafora disease to apply gene therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment through neuropathological studies, behavioral tests, video-electroencephalography, electrophysiological recordings, and proteomic/phosphoproteomic analysis. Gene therapy ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Moreover, differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Our results represent proof of principle for gene therapy with the coding region of the human EPM2A gene as a treatment for EPM2A-related Lafora disease. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 2025 2025 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/396187 https://api.elsevier.com/content/abstract/scopus_id/85196057293 |
| url |
http://hdl.handle.net/10261/396187 https://api.elsevier.com/content/abstract/scopus_id/85196057293 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095784-B-I00 The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.ymthe.2024.05.032 https://doi.org/10.1016/j.ymthe.2024.05.032 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Cell Press |
| publisher.none.fl_str_mv |
Cell Press |
| dc.source.none.fl_str_mv |
reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
| instname_str |
Consejo Superior de Investigaciones Científicas (CSIC) |
| reponame_str |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
| collection |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869423919623045120 |
| spelling |
Gene therapy for Lafora disease in the Epm2a-/- mouse modelZafra-Puerta, LuisIglesias-Cabeza, NereaBurgos, Daniel F.Sciaccaluga, MiriamGonzález-Fernández, JuanBellingacci, LauraCanonichesi, JacopoSánchez-Martín, GemaCosta, CinziaSánchez, Marina P.Serratosa, José M.Epm2a(−/−) knockout mouseGene therapyLaforinpolyglucosansProgressive myoclonic epilepsyrAAVhttp://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesLafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. The disease results from mutations in the EPM2A gene, encoding laforin, or the EPM2B gene, encoding malin. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein cause alterations in this complex, leading to the formation of Lafora bodies containing abnormal, insoluble, and hyperphosphorylated forms of glycogen. We used the Epm2a-/- knockout mouse model of Lafora disease to apply gene therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment through neuropathological studies, behavioral tests, video-electroencephalography, electrophysiological recordings, and proteomic/phosphoproteomic analysis. Gene therapy ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Moreover, differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Our results represent proof of principle for gene therapy with the coding region of the human EPM2A gene as a treatment for EPM2A-related Lafora disease.This work was supported by grants from the Spanish Ministry of Economy (Rti2018-095784b-100SAF MCI/AEI/FEDER, UE) to J.M.S. and M.P.S.; from the Tatiana Perez de Guzman el Bueno Foundation to M.P.S. and J.M.S.; from the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (ACCI 2020, 23 - U744) to M.P.S.; from the Fondazione Malattie Rare Mauro Baschirotto BIRD Onlus to M.P.S., C.C., M.S., and L.Z.P.; and a grant from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (P01NS097197), which established the Lafora Epilepsy Cure Initiative (LECI), to J.M.S. and M.P.S. We thank Pascual Sanz Bigorra (Institute of Biomedicine of Valencia [IBV]) and Manuel Soto Catalán (Instituto de Investigación Sanitaria-Fundación Jiménez Díaz) for their generous gift of GS, BiP, and cleaved caspase-3 antibodies, and to Miguel Chillón Rodríguez (Viral Vector Production Unit or UPV-UAB-VHIR) for the generation of rAAVs and technical advice. We also thank Juan Antonio López del Olmo (CNIC Proteomics Unit), Ariadna Martín Blázquez (Instituto de Investigación Sanitaria-Fundación Jiménez Díaz), and the Animal Facility of Instituto de Investigación Sanitaria-Fundación Jiménez Díaz for their technical assistance.Peer reviewedCell PressMinisterio de Economía y Competitividad (España)Fundación Tatiana Pérez de Guzmán el BuenoCentro de Investigación Biomédica en Red Enfermedades Raras (España)BIRD FoundationNational Institute of Neurological Disorders and Stroke (US)CSIC - Instituto de Biomedicina de Valencia (IBV)Hospital Universitario Fundación Jiménez DíazZafra-Puerta, Luis [0000-0002-1807-7538]Serratosa, José M. [0000-0003-2239-8948]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/396187https://api.elsevier.com/content/abstract/scopus_id/85196057293reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095784-B-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.ymthe.2024.05.032https://doi.org/10.1016/j.ymthe.2024.05.032Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3961872026-05-22T06:33:51Z |
| score |
15.811543 |