High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy

Abstract Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could signific...

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Autores principales:	A. M. Kivelä, J. Huusko, E. Gurzeler, A. Laine, M. H. Dijkstra, G. Dragneva, C. B. F. Andersen, S. K. Moestrup, S. Ylä-Herttuala
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/13eec640ea744d0e8b268a995fb998d0
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spelling	oai:doaj.org-article:13eec640ea744d0e8b268a995fb998d02021-12-02T11:40:34ZHigh Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy10.1038/s41598-017-00376-52045-2322https://doaj.org/article/13eec640ea744d0e8b268a995fb998d02017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00376-5https://doaj.org/toc/2045-2322Abstract Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE−/− mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors.A. M. KiveläJ. HuuskoE. GurzelerA. LaineM. H. DijkstraG. DragnevaC. B. F. AndersenS. K. MoestrupS. Ylä-HerttualaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q A. M. Kivelä J. Huusko E. Gurzeler A. Laine M. H. Dijkstra G. Dragneva C. B. F. Andersen S. K. Moestrup S. Ylä-Herttuala High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy
description	Abstract Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE−/− mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors.
format	article
author	A. M. Kivelä J. Huusko E. Gurzeler A. Laine M. H. Dijkstra G. Dragneva C. B. F. Andersen S. K. Moestrup S. Ylä-Herttuala
author_facet	A. M. Kivelä J. Huusko E. Gurzeler A. Laine M. H. Dijkstra G. Dragneva C. B. F. Andersen S. K. Moestrup S. Ylä-Herttuala
author_sort	A. M. Kivelä
title	High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy
title_short	High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy
title_full	High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy
title_fullStr	High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy
title_full_unstemmed	High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy
title_sort	high plasma lipid levels reduce efficacy of adenovirus-mediated gene therapy
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/13eec640ea744d0e8b268a995fb998d0
work_keys_str_mv	AT amkivela highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT jhuusko highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT egurzeler highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT alaine highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT mhdijkstra highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT gdragneva highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT cbfandersen highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT skmoestrup highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy AT sylaherttuala highplasmalipidlevelsreduceefficacyofadenovirusmediatedgenetherapy
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High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy

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