Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.

Liver-directed gene transfer is being investigated for the treatment of systemic or liver-specific diseases. Recombinant vectors based on adeno-associated virus serotype 8 (AAV2/8) efficiently transduce liver cells allowing long term transgene expression after a single administration in animal model...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Gabriella Cotugno, Patrizia Annunziata, Maria Vittoria Barone, Marianthi Karali, Sandro Banfi, Alberto Auricchio
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a03f2ebf161546d1b2099161ca58d6a7
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a03f2ebf161546d1b2099161ca58d6a7
record_format	dspace
spelling	oai:doaj.org-article:a03f2ebf161546d1b2099161ca58d6a72021-11-18T07:25:17ZImpact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.1932-620310.1371/journal.pone.0033286https://doaj.org/article/a03f2ebf161546d1b2099161ca58d6a72012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22428010/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Liver-directed gene transfer is being investigated for the treatment of systemic or liver-specific diseases. Recombinant vectors based on adeno-associated virus serotype 8 (AAV2/8) efficiently transduce liver cells allowing long term transgene expression after a single administration in animal models and in patients.We evaluated the impact on AAV2/8-mediated rat liver transduction of the following variables: i) age at vector administration, ii) presence of lysosomal storage in liver cells, and iii) regulatory elements included in the transgene expression cassette. We found that systemic administration of AAV2/8 to newborn rats results in vector genome dilution and reduced transduction efficacy when compared to adult injected animals, presumably due to hepatocyte proliferation. Accumulation of glycosaminoglycans in lysosomes does not impact on levels and distribution of AAV2/8-mediated liver transduction. Transgene expression occurs in hepatocytes but not in Kupffer or liver endothelial cells when the liver-specific thyroxine-binding-globulin promoter is used. However, extra-hepatic transduction is observed in the spleen and kidney of animals injected at birth. The use of target sequences for the hematopoietic-specific microRNA miR142-3p does not improve liver transduction efficacy neither reduce immune responses to the lysosomal enzyme arylsulfatase B. The inclusion of a variant of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE-m) decreases AAV2/8-mediated liver transduction levels.As AAV2/8-mediated liver gene transfer is entering in the clinical arena, these data will provide relevant information to the design of efficient AAV2/8-based therapeutic strategies.Gabriella CotugnoPatrizia AnnunziataMaria Vittoria BaroneMarianthi KaraliSandro BanfiAlberto AuricchioPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e33286 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabriella Cotugno Patrizia Annunziata Maria Vittoria Barone Marianthi Karali Sandro Banfi Alberto Auricchio Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.
description	Liver-directed gene transfer is being investigated for the treatment of systemic or liver-specific diseases. Recombinant vectors based on adeno-associated virus serotype 8 (AAV2/8) efficiently transduce liver cells allowing long term transgene expression after a single administration in animal models and in patients.We evaluated the impact on AAV2/8-mediated rat liver transduction of the following variables: i) age at vector administration, ii) presence of lysosomal storage in liver cells, and iii) regulatory elements included in the transgene expression cassette. We found that systemic administration of AAV2/8 to newborn rats results in vector genome dilution and reduced transduction efficacy when compared to adult injected animals, presumably due to hepatocyte proliferation. Accumulation of glycosaminoglycans in lysosomes does not impact on levels and distribution of AAV2/8-mediated liver transduction. Transgene expression occurs in hepatocytes but not in Kupffer or liver endothelial cells when the liver-specific thyroxine-binding-globulin promoter is used. However, extra-hepatic transduction is observed in the spleen and kidney of animals injected at birth. The use of target sequences for the hematopoietic-specific microRNA miR142-3p does not improve liver transduction efficacy neither reduce immune responses to the lysosomal enzyme arylsulfatase B. The inclusion of a variant of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE-m) decreases AAV2/8-mediated liver transduction levels.As AAV2/8-mediated liver gene transfer is entering in the clinical arena, these data will provide relevant information to the design of efficient AAV2/8-based therapeutic strategies.
format	article
author	Gabriella Cotugno Patrizia Annunziata Maria Vittoria Barone Marianthi Karali Sandro Banfi Alberto Auricchio
author_facet	Gabriella Cotugno Patrizia Annunziata Maria Vittoria Barone Marianthi Karali Sandro Banfi Alberto Auricchio
author_sort	Gabriella Cotugno
title	Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.
title_short	Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.
title_full	Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.
title_fullStr	Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.
title_full_unstemmed	Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.
title_sort	impact of age at administration, lysosomal storage, and transgene regulatory elements on aav2/8-mediated rat liver transduction.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/a03f2ebf161546d1b2099161ca58d6a7
work_keys_str_mv	AT gabriellacotugno impactofageatadministrationlysosomalstorageandtransgeneregulatoryelementsonaav28mediatedratlivertransduction AT patriziaannunziata impactofageatadministrationlysosomalstorageandtransgeneregulatoryelementsonaav28mediatedratlivertransduction AT mariavittoriabarone impactofageatadministrationlysosomalstorageandtransgeneregulatoryelementsonaav28mediatedratlivertransduction AT marianthikarali impactofageatadministrationlysosomalstorageandtransgeneregulatoryelementsonaav28mediatedratlivertransduction AT sandrobanfi impactofageatadministrationlysosomalstorageandtransgeneregulatoryelementsonaav28mediatedratlivertransduction AT albertoauricchio impactofageatadministrationlysosomalstorageandtransgeneregulatoryelementsonaav28mediatedratlivertransduction
_version_	1718423491674374144

Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.

Ejemplares similares