Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides

Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so...

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Autores: Vila-Julià, Ferran, Cabrera-Pérez, Raquel|||0000-0002-4858-0142, Cámara, Yolanda|||0000-0003-2458-6942, Molina-Berenguer, Miguel|||0000-0001-8087-4709, Lope-Piedrafita, Silvia|||0000-0002-8127-6425, Hirano, Michio|||0000-0002-7070-7402, Mingozzi, Federico, Torres-Torronteras, Javier|||0000-0002-6092-9458, Martí, Ramon A.|||0000-0002-8273-9540
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:238660
Acceso en línea:https://ddd.uab.cat/record/238660
https://dx.doi.org/urn:doi:10.1016/j.ebiom.2020.103133
Access Level:acceso abierto
Palabra clave:MNGIE
Gene therapy
Nucleosides
Mitochondrial disease
Thymidine phosphorylase
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spelling Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosidesVila-Julià, FerranCabrera-Pérez, Raquel|||0000-0002-4858-0142Cámara, Yolanda|||0000-0003-2458-6942Molina-Berenguer, Miguel|||0000-0001-8087-4709Lope-Piedrafita, Silvia|||0000-0002-8127-6425Hirano, Michio|||0000-0002-7070-7402Mingozzi, FedericoTorres-Torronteras, Javier|||0000-0002-6092-9458Martí, Ramon A.|||0000-0002-8273-9540MNGIEGene therapyNucleosidesMitochondrial diseaseThymidine phosphorylasePreclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches. dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals. Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy. Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype. This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 22020-01-0120202020-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/238660https://dx.doi.org/urn:doi:10.1016/j.ebiom.2020.103133reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18-01574Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI15-00465Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2018FI-B-01115open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2386602026-06-06T12:50:31Z
dc.title.none.fl_str_mv Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
title Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
spellingShingle Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
Vila-Julià, Ferran
MNGIE
Gene therapy
Nucleosides
Mitochondrial disease
Thymidine phosphorylase
title_short Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
title_full Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
title_fullStr Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
title_full_unstemmed Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
title_sort Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides
dc.creator.none.fl_str_mv Vila-Julià, Ferran
Cabrera-Pérez, Raquel|||0000-0002-4858-0142
Cámara, Yolanda|||0000-0003-2458-6942
Molina-Berenguer, Miguel|||0000-0001-8087-4709
Lope-Piedrafita, Silvia|||0000-0002-8127-6425
Hirano, Michio|||0000-0002-7070-7402
Mingozzi, Federico
Torres-Torronteras, Javier|||0000-0002-6092-9458
Martí, Ramon A.|||0000-0002-8273-9540
author Vila-Julià, Ferran
author_facet Vila-Julià, Ferran
Cabrera-Pérez, Raquel|||0000-0002-4858-0142
Cámara, Yolanda|||0000-0003-2458-6942
Molina-Berenguer, Miguel|||0000-0001-8087-4709
Lope-Piedrafita, Silvia|||0000-0002-8127-6425
Hirano, Michio|||0000-0002-7070-7402
Mingozzi, Federico
Torres-Torronteras, Javier|||0000-0002-6092-9458
Martí, Ramon A.|||0000-0002-8273-9540
author_role author
author2 Cabrera-Pérez, Raquel|||0000-0002-4858-0142
Cámara, Yolanda|||0000-0003-2458-6942
Molina-Berenguer, Miguel|||0000-0001-8087-4709
Lope-Piedrafita, Silvia|||0000-0002-8127-6425
Hirano, Michio|||0000-0002-7070-7402
Mingozzi, Federico
Torres-Torronteras, Javier|||0000-0002-6092-9458
Martí, Ramon A.|||0000-0002-8273-9540
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MNGIE
Gene therapy
Nucleosides
Mitochondrial disease
Thymidine phosphorylase
topic MNGIE
Gene therapy
Nucleosides
Mitochondrial disease
Thymidine phosphorylase
description Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches. dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals. Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy. Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype. This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
publishDate 2020
dc.date.none.fl_str_mv 2
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/238660
https://dx.doi.org/urn:doi:10.1016/j.ebiom.2020.103133
url https://ddd.uab.cat/record/238660
https://dx.doi.org/urn:doi:10.1016/j.ebiom.2020.103133
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18-01574
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI15-00465
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2018FI-B-01115
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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