Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model

Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. Wh...

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Autores: Mateu-Bosch, Anna, Segur-Bailach, Eulàlia, Muñoz-Moreno, Emma, Barallobre, María-José, Arbones, Maria L., Gea-Sorlí, Sabrina, Tort, Frederic, Ribes, Antonia, García-Villoria, Judit, Fillat, Cristina
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:10261/375619
Acceso en línea:http://hdl.handle.net/10261/375619
Access Level:acceso abierto
Palabra clave:Glutaric aciduria
Metabolic disease
Viral vectors
Gene replacement
Adeno-associated virus
AAV
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dc.title.none.fl_str_mv Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
title Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
spellingShingle Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
Mateu-Bosch, Anna
Glutaric aciduria
Metabolic disease
Viral vectors
Gene replacement
Adeno-associated virus
AAV
title_short Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
title_full Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
title_fullStr Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
title_full_unstemmed Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
title_sort Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model
dc.creator.none.fl_str_mv Mateu-Bosch, Anna
Segur-Bailach, Eulàlia
Muñoz-Moreno, Emma
Barallobre, María-José
Arbones, Maria L.
Gea-Sorlí, Sabrina
Tort, Frederic
Ribes, Antonia
García-Villoria, Judit
Fillat, Cristina
author Mateu-Bosch, Anna
author_facet Mateu-Bosch, Anna
Segur-Bailach, Eulàlia
Muñoz-Moreno, Emma
Barallobre, María-José
Arbones, Maria L.
Gea-Sorlí, Sabrina
Tort, Frederic
Ribes, Antonia
García-Villoria, Judit
Fillat, Cristina
author_role author
author2 Segur-Bailach, Eulàlia
Muñoz-Moreno, Emma
Barallobre, María-José
Arbones, Maria L.
Gea-Sorlí, Sabrina
Tort, Frederic
Ribes, Antonia
García-Villoria, Judit
Fillat, Cristina
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Centro Esther Koplowitz
Fundación Ramón Areces
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Fundación la Caixa
Generalitat de Catalunya
Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Glutaric aciduria
Metabolic disease
Viral vectors
Gene replacement
Adeno-associated virus
AAV
topic Glutaric aciduria
Metabolic disease
Viral vectors
Gene replacement
Adeno-associated virus
AAV
description Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. While early diagnosis and a lysine restricted diet can extend survival, they do not prevent neurological damage in approximately one-third of treated patients, and more effective therapies are required. Here we report the efficacy of adeno-associated virus 9 (AAV9)-mediated systemic delivery of human GCDH at preventing a high lysine diet (HLD)-induced phenotype in Gcdh−/− mice. Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. This treatment protects the mice from HLD-aggressive phenotype with all mice surviving this exposure; in stark contrast, a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. Magnetic resonance imaging findings show protection against striatal injury. Altogether, these results provide preclinical evidence to support AAV-GCDH gene therapy for GA1.
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/10261/375619
url http://hdl.handle.net/10261/375619
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119692RB-C22
info:eu-repo/grantAgreement/EC/H2020/825575
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.omtm.2024.101276
Panadero Soler, Daniel; Kotb Selim, Mohamed; Martínez-Tazo, Patricia; Muñoz-Moreno, Emma; Ramos-Cabrer, Pedro; López-Larrubia, Pilar; De Santis, Silvia; Canals, Santiago; Pertusa, Antonio; 2025; SAMson: an automated brain extraction tool for rodents using SAM [Dataset]; DIGITAL.CSIC; DOI
https://doi.org/10.1016/j.omtm.2024.101276
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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dc.publisher.none.fl_str_mv Elsevier
American Society of Gene and Cell Therapy
publisher.none.fl_str_mv Elsevier
American Society of Gene and Cell Therapy
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
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spelling Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse modelMateu-Bosch, AnnaSegur-Bailach, EulàliaMuñoz-Moreno, EmmaBarallobre, María-JoséArbones, Maria L.Gea-Sorlí, SabrinaTort, FredericRibes, AntoniaGarcía-Villoria, JuditFillat, CristinaGlutaric aciduriaMetabolic diseaseViral vectorsGene replacementAdeno-associated virusAAVGlutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. While early diagnosis and a lysine restricted diet can extend survival, they do not prevent neurological damage in approximately one-third of treated patients, and more effective therapies are required. Here we report the efficacy of adeno-associated virus 9 (AAV9)-mediated systemic delivery of human GCDH at preventing a high lysine diet (HLD)-induced phenotype in Gcdh−/− mice. Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. This treatment protects the mice from HLD-aggressive phenotype with all mice surviving this exposure; in stark contrast, a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. Magnetic resonance imaging findings show protection against striatal injury. Altogether, these results provide preclinical evidence to support AAV-GCDH gene therapy for GA1.This work was developed at the Centro Esther Koplowitz, Barcelona, Spain. A.M.-B. is the recipient of a PIF-Salut predoctoral contract from Generalitat de Catalunya, Spain. This work was supported by grants to CF from the CIVP19A5949-Fundación Ramón Areces, ACCI-CIBERER, and PID2020-119692RB-C22 Spanish Ministerio de Ciencia e Innovación, with partial support from Fundacio La Caixa, the Generalitat de Catalunya SGR21/01169 and from ISCIII RICORS RD21/0017/0012. We also acknowledge all members of the CHARLIE Consortium (www.charlie.science) for their helpful discussions. This project also received support from Instituto de Salud Carlos III (ISCIII) AC20/00088 under the frame of E-Rare-3, the ERA-Net for Research on Rare Diseases, EJPRD (grant nr: 825575). CIBERER is an initiative of the ISCIII. We also acknowledge the support of CERCA Programme/Generalitat de Catalunya. Graphical abstract was created with Biorender.com.Peer reviewedElsevierAmerican Society of Gene and Cell TherapyCentro Esther KoplowitzFundación Ramón ArecesMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Fundación la CaixaGeneralitat de CatalunyaInstituto de Salud Carlos IIIEuropean CommissionConsejo 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/10261/375619reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119692RB-C22info:eu-repo/grantAgreement/EC/H2020/825575The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.omtm.2024.101276Panadero Soler, Daniel; Kotb Selim, Mohamed; Martínez-Tazo, Patricia; Muñoz-Moreno, Emma; Ramos-Cabrer, Pedro; López-Larrubia, Pilar; De Santis, Silvia; Canals, Santiago; Pertusa, Antonio; 2025; SAMson: an automated brain extraction tool for rodents using SAM [Dataset]; DIGITAL.CSIC; DOIhttps://doi.org/10.1016/j.omtm.2024.101276Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3756192026-05-22T06:33:51Z
score 15,811543

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