Glial promoter selectivity following AAV-delivery to the immature brain.

Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However,...

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Autores principales:	Georg von Jonquieres, Nadine Mersmann, Claudia Bettina Klugmann, Anne Editha Harasta, Beat Lutz, Orla Teahan, Gary David Housley, Dominik Fröhlich, Eva-Maria Krämer-Albers, Matthias Klugmann
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/984f0a8c0abe433b9effcce3f16e096b
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spelling	oai:doaj.org-article:984f0a8c0abe433b9effcce3f16e096b2021-11-18T07:41:43ZGlial promoter selectivity following AAV-delivery to the immature brain.1932-620310.1371/journal.pone.0065646https://doaj.org/article/984f0a8c0abe433b9effcce3f16e096b2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23799030/?tool=EBIhttps://doaj.org/toc/1932-6203Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However, neurological disorders caused by glial pathology usually have an early onset. Therefore, modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS. Here, we have investigated the AAV-mediated green fluorescent protein (GFP) expression driven by the myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters in the developing mouse brain. Generally, the extent of transgene expression after infusion at immature stages was widespread and higher than in adults. The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults. In contrast, the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery, but excellent after vector injection at postnatal day 10. To extend these findings obtained in naïve mice to a disease model, we performed P10 infusions of AAV-MBP-GFP in aspartoacylase (ASPA)-deficient mouse mutants presenting with early onset oligodendrocyte pathology. Spread of GFP expression and selectivity for oligodendrocytes in ASPA-mutants was comparable with our observations in normal animals. Our data suggest that direct AAV infusion to the developing postnatal brain, utilising cellular promoters, results in targeted and long-term transgene expression in glia. This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology.Georg von JonquieresNadine MersmannClaudia Bettina KlugmannAnne Editha HarastaBeat LutzOrla TeahanGary David HousleyDominik FröhlichEva-Maria Krämer-AlbersMatthias KlugmannPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e65646 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Georg von Jonquieres Nadine Mersmann Claudia Bettina Klugmann Anne Editha Harasta Beat Lutz Orla Teahan Gary David Housley Dominik Fröhlich Eva-Maria Krämer-Albers Matthias Klugmann Glial promoter selectivity following AAV-delivery to the immature brain.
description	Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However, neurological disorders caused by glial pathology usually have an early onset. Therefore, modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS. Here, we have investigated the AAV-mediated green fluorescent protein (GFP) expression driven by the myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters in the developing mouse brain. Generally, the extent of transgene expression after infusion at immature stages was widespread and higher than in adults. The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults. In contrast, the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery, but excellent after vector injection at postnatal day 10. To extend these findings obtained in naïve mice to a disease model, we performed P10 infusions of AAV-MBP-GFP in aspartoacylase (ASPA)-deficient mouse mutants presenting with early onset oligodendrocyte pathology. Spread of GFP expression and selectivity for oligodendrocytes in ASPA-mutants was comparable with our observations in normal animals. Our data suggest that direct AAV infusion to the developing postnatal brain, utilising cellular promoters, results in targeted and long-term transgene expression in glia. This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology.
format	article
author	Georg von Jonquieres Nadine Mersmann Claudia Bettina Klugmann Anne Editha Harasta Beat Lutz Orla Teahan Gary David Housley Dominik Fröhlich Eva-Maria Krämer-Albers Matthias Klugmann
author_facet	Georg von Jonquieres Nadine Mersmann Claudia Bettina Klugmann Anne Editha Harasta Beat Lutz Orla Teahan Gary David Housley Dominik Fröhlich Eva-Maria Krämer-Albers Matthias Klugmann
author_sort	Georg von Jonquieres
title	Glial promoter selectivity following AAV-delivery to the immature brain.
title_short	Glial promoter selectivity following AAV-delivery to the immature brain.
title_full	Glial promoter selectivity following AAV-delivery to the immature brain.
title_fullStr	Glial promoter selectivity following AAV-delivery to the immature brain.
title_full_unstemmed	Glial promoter selectivity following AAV-delivery to the immature brain.
title_sort	glial promoter selectivity following aav-delivery to the immature brain.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/984f0a8c0abe433b9effcce3f16e096b
work_keys_str_mv	AT georgvonjonquieres glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT nadinemersmann glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT claudiabettinaklugmann glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT anneedithaharasta glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT beatlutz glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT orlateahan glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT garydavidhousley glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT dominikfrohlich glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT evamariakrameralbers glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain AT matthiasklugmann glialpromoterselectivityfollowingaavdeliverytotheimmaturebrain
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Glial promoter selectivity following AAV-delivery to the immature brain.

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