Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.

<h4>Background</h4>Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and a...

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Autores principales: Sadik H Kassim, Hui Li, Luk H Vandenberghe, Christian Hinderer, Peter Bell, Dawn Marchadier, Aisha Wilson, Debra Cromley, Valeska Redon, Hongwei Yu, James M Wilson, Daniel J Rader
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Publicado: Public Library of Science (PLoS) 2010
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spelling oai:doaj.org-article:e79587d53a7b4820b632c5dfd2a0f4832021-11-18T07:03:08ZGene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.1932-620310.1371/journal.pone.0013424https://doaj.org/article/e79587d53a7b4820b632c5dfd2a0f4832010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20976059/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and adolescence. Mice with germ line interruptions in the Ldlr and Apobec1 genes (Ldlr(-/-)Apobec1(-/-)) simulate metabolic and clinical aspects of hoFH, including atherogenesis on a chow diet.<h4>Methods/principal findings</h4>In this study, vectors based on adeno-associated virus 8 (AAV8) were used to deliver the gene for mouse Ldlr (mLDLR) to the livers of Ldlr(-/-)Apobec1(-/-) mice. A single intravenous injection of AAV8.mLDLR was found to significantly reduce plasma cholesterol and non-HDL cholesterol levels in chow-fed animals at doses as low as 3×10(9) genome copies/mouse. Whereas Ldlr(-/-)Apobec1(-/-) mice fed a western-type diet and injected with a control AAV8.null vector experienced a further 65% progression in atherosclerosis over 2 months compared with baseline mice, Ldlr(-/-)Apobec1(-/-) mice treated with AAV8.mLDLR realized an 87% regression of atherosclerotic lesions after 3 months compared to baseline mice. Immunohistochemical analyses revealed a substantial remodeling of atherosclerotic lesions.<h4>Conclusions/significance</h4>Collectively, the results presented herein suggest that AAV8-based gene therapy for FH may be feasible and support further development of this approach. The pre-clinical data from these studies will enable for the effective translation of gene therapy into the clinic for treatment of FH.Sadik H KassimHui LiLuk H VandenbergheChristian HindererPeter BellDawn MarchadierAisha WilsonDebra CromleyValeska RedonHongwei YuJames M WilsonDaniel J RaderPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13424 (2010)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Sadik H Kassim
Hui Li
Luk H Vandenberghe
Christian Hinderer
Peter Bell
Dawn Marchadier
Aisha Wilson
Debra Cromley
Valeska Redon
Hongwei Yu
James M Wilson
Daniel J Rader
Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
description <h4>Background</h4>Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and adolescence. Mice with germ line interruptions in the Ldlr and Apobec1 genes (Ldlr(-/-)Apobec1(-/-)) simulate metabolic and clinical aspects of hoFH, including atherogenesis on a chow diet.<h4>Methods/principal findings</h4>In this study, vectors based on adeno-associated virus 8 (AAV8) were used to deliver the gene for mouse Ldlr (mLDLR) to the livers of Ldlr(-/-)Apobec1(-/-) mice. A single intravenous injection of AAV8.mLDLR was found to significantly reduce plasma cholesterol and non-HDL cholesterol levels in chow-fed animals at doses as low as 3×10(9) genome copies/mouse. Whereas Ldlr(-/-)Apobec1(-/-) mice fed a western-type diet and injected with a control AAV8.null vector experienced a further 65% progression in atherosclerosis over 2 months compared with baseline mice, Ldlr(-/-)Apobec1(-/-) mice treated with AAV8.mLDLR realized an 87% regression of atherosclerotic lesions after 3 months compared to baseline mice. Immunohistochemical analyses revealed a substantial remodeling of atherosclerotic lesions.<h4>Conclusions/significance</h4>Collectively, the results presented herein suggest that AAV8-based gene therapy for FH may be feasible and support further development of this approach. The pre-clinical data from these studies will enable for the effective translation of gene therapy into the clinic for treatment of FH.
format article
author Sadik H Kassim
Hui Li
Luk H Vandenberghe
Christian Hinderer
Peter Bell
Dawn Marchadier
Aisha Wilson
Debra Cromley
Valeska Redon
Hongwei Yu
James M Wilson
Daniel J Rader
author_facet Sadik H Kassim
Hui Li
Luk H Vandenberghe
Christian Hinderer
Peter Bell
Dawn Marchadier
Aisha Wilson
Debra Cromley
Valeska Redon
Hongwei Yu
James M Wilson
Daniel J Rader
author_sort Sadik H Kassim
title Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
title_short Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
title_full Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
title_fullStr Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
title_full_unstemmed Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
title_sort gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/e79587d53a7b4820b632c5dfd2a0f483
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