Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis
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...
Gespeichert in:
| Veröffentlicht in: | PloS one 2010-10, Vol.5 (10), p.e13424-e13424 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e13424 |
|---|---|
| container_issue | 10 |
| container_start_page | e13424 |
| container_title | PloS one |
| container_volume | 5 |
| creator | Kassim, Sadik H Li, Hui Vandenberghe, Luk H Hinderer, Christian Bell, Peter Marchadier, Dawn Wilson, Aisha Cromley, Debra Redon, Valeska Yu, Hongwei Wilson, James M Rader, Daniel J |
| description | 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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0013424 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1292194354</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A473846713</galeid><doaj_id>oai_doaj_org_article_e79587d53a7b4820b632c5dfd2a0f483</doaj_id><sourcerecordid>A473846713</sourcerecordid><originalsourceid>FETCH-LOGICAL-c789t-1e59b20139d988688a2a60c01462cd0b3743a2f72e9009f29d6a725f86b080f93</originalsourceid><addsrcrecordid>eNqNk_1r1DAYx4sobk7_A9GCoPjDnXltk1-EMXQeDAa-_RqeNuk1M21uSTs8_3pT7zauMlAKSUg_3yfPa5Y9x2iJaYnfXfkx9OCWG9-bJUKYMsIeZMdYUrIoCKIPD85H2ZMYrxDiVBTF4-yIIFkWiMvj7Obc9CYfWhNgs81tn0Pejh309pfReefHaNKqjct9kzfQWWfB5e12Y0LdemfiYELaOgu5M6BjPvi8g_AjiYNZBxOj9f2khekJH2s3rTY-zR414KJ5tt9Psm8fP3w9-7S4uDxfnZ1eLOpSyGGBDZcVSbFJLYUohAACBaoRZgWpNapoySiQpiRGIiQbInUBJeGNKCokUCPpSfZyZ3fjfFT7lEWFiSRYMspZIlY7Qnu4Uptgk_tb5cGqPxc-rBWEwSbHlSklF6XmFMqKCYKqgpKa60YTQA0TNNl6v39trDqja9MPAdzM6PxPb1u19jeKSJ4imQy82RsI_npM2VWdjbVxDnqTaqEkZ1wSIfE_yVReghHGPJGv_iLvT8OeWkOK1PaNTw7Wk011ykoqWFHiyb_lPVT6dGqBOjViY9P9TPB2JkjMYH4OaxhjVKsvn_-fvfw-Z18fsK0BN7TRu3FI7RbnINuBdeq7GExzVw2M1DRHt9lQ0xyp_Rwl2YvDSt6JbgeH_gYPsxge</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1292194354</pqid></control><display><type>article</type><title>Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis</title><source>Public Library of Science (PLoS) Journals Open Access</source><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Kassim, Sadik H ; Li, Hui ; Vandenberghe, Luk H ; Hinderer, Christian ; Bell, Peter ; Marchadier, Dawn ; Wilson, Aisha ; Cromley, Debra ; Redon, Valeska ; Yu, Hongwei ; Wilson, James M ; Rader, Daniel J</creator><creatorcontrib>Kassim, Sadik H ; Li, Hui ; Vandenberghe, Luk H ; Hinderer, Christian ; Bell, Peter ; Marchadier, Dawn ; Wilson, Aisha ; Cromley, Debra ; Redon, Valeska ; Yu, Hongwei ; Wilson, James M ; Rader, Daniel J</creatorcontrib><description>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.
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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0013424</identifier><identifier>PMID: 20976059</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adeno-associated virus ; Adolescence ; Adolescents ; Analysis ; Animals ; Antigens ; Arteriosclerosis ; Atherogenesis ; Atherosclerosis ; Atherosclerosis - therapy ; Base Sequence ; Blood cholesterol ; Cardiovascular Disorders ; Children ; Cholesterol ; Clinical aspects ; Computer simulation ; Disease Models, Animal ; DNA Primers ; Epidemiology ; Gastroenterology and Hepatology/Hepatology ; Gene therapy ; Genes ; Genetic aspects ; Genetic Therapy ; Genetics and Genomics/Gene Therapy ; Genetics and Genomics/Genetics of Disease ; Genomes ; Hemophilia ; High density lipoprotein ; House mouse ; Humans ; Hypercholesterolemia ; Hyperlipoproteinemia Type II - therapy ; Immunohistochemistry ; Intravenous administration ; Laboratories ; Lesions ; Low density lipoprotein receptors ; Low density lipoproteins ; Lymphocytes ; Male ; Medicine ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Pathology ; Receptor density ; Receptors, LDL - genetics ; Regression analysis ; Translation (Genetics) ; Vectors (Biology) ; Viruses</subject><ispartof>PloS one, 2010-10, Vol.5 (10), p.e13424-e13424</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>2010 Kassim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Kassim et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c789t-1e59b20139d988688a2a60c01462cd0b3743a2f72e9009f29d6a725f86b080f93</citedby><cites>FETCH-LOGICAL-c789t-1e59b20139d988688a2a60c01462cd0b3743a2f72e9009f29d6a725f86b080f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957433/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957433/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20976059$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kassim, Sadik H</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Vandenberghe, Luk H</creatorcontrib><creatorcontrib>Hinderer, Christian</creatorcontrib><creatorcontrib>Bell, Peter</creatorcontrib><creatorcontrib>Marchadier, Dawn</creatorcontrib><creatorcontrib>Wilson, Aisha</creatorcontrib><creatorcontrib>Cromley, Debra</creatorcontrib><creatorcontrib>Redon, Valeska</creatorcontrib><creatorcontrib>Yu, Hongwei</creatorcontrib><creatorcontrib>Wilson, James M</creatorcontrib><creatorcontrib>Rader, Daniel J</creatorcontrib><title>Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.</description><subject>Adeno-associated virus</subject><subject>Adolescence</subject><subject>Adolescents</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antigens</subject><subject>Arteriosclerosis</subject><subject>Atherogenesis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - therapy</subject><subject>Base Sequence</subject><subject>Blood cholesterol</subject><subject>Cardiovascular Disorders</subject><subject>Children</subject><subject>Cholesterol</subject><subject>Clinical aspects</subject><subject>Computer simulation</subject><subject>Disease Models, Animal</subject><subject>DNA Primers</subject><subject>Epidemiology</subject><subject>Gastroenterology and Hepatology/Hepatology</subject><subject>Gene therapy</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Therapy</subject><subject>Genetics and Genomics/Gene Therapy</subject><subject>Genetics and Genomics/Genetics of Disease</subject><subject>Genomes</subject><subject>Hemophilia</subject><subject>High density lipoprotein</subject><subject>House mouse</subject><subject>Humans</subject><subject>Hypercholesterolemia</subject><subject>Hyperlipoproteinemia Type II - therapy</subject><subject>Immunohistochemistry</subject><subject>Intravenous administration</subject><subject>Laboratories</subject><subject>Lesions</subject><subject>Low density lipoprotein receptors</subject><subject>Low density lipoproteins</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mutation</subject><subject>Pathology</subject><subject>Receptor density</subject><subject>Receptors, LDL - genetics</subject><subject>Regression analysis</subject><subject>Translation (Genetics)</subject><subject>Vectors (Biology)</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk_1r1DAYx4sobk7_A9GCoPjDnXltk1-EMXQeDAa-_RqeNuk1M21uSTs8_3pT7zauMlAKSUg_3yfPa5Y9x2iJaYnfXfkx9OCWG9-bJUKYMsIeZMdYUrIoCKIPD85H2ZMYrxDiVBTF4-yIIFkWiMvj7Obc9CYfWhNgs81tn0Pejh309pfReefHaNKqjct9kzfQWWfB5e12Y0LdemfiYELaOgu5M6BjPvi8g_AjiYNZBxOj9f2khekJH2s3rTY-zR414KJ5tt9Psm8fP3w9-7S4uDxfnZ1eLOpSyGGBDZcVSbFJLYUohAACBaoRZgWpNapoySiQpiRGIiQbInUBJeGNKCokUCPpSfZyZ3fjfFT7lEWFiSRYMspZIlY7Qnu4Uptgk_tb5cGqPxc-rBWEwSbHlSklF6XmFMqKCYKqgpKa60YTQA0TNNl6v39trDqja9MPAdzM6PxPb1u19jeKSJ4imQy82RsI_npM2VWdjbVxDnqTaqEkZ1wSIfE_yVReghHGPJGv_iLvT8OeWkOK1PaNTw7Wk011ykoqWFHiyb_lPVT6dGqBOjViY9P9TPB2JkjMYH4OaxhjVKsvn_-fvfw-Z18fsK0BN7TRu3FI7RbnINuBdeq7GExzVw2M1DRHt9lQ0xyp_Rwl2YvDSt6JbgeH_gYPsxge</recordid><startdate>20101019</startdate><enddate>20101019</enddate><creator>Kassim, Sadik H</creator><creator>Li, Hui</creator><creator>Vandenberghe, Luk H</creator><creator>Hinderer, Christian</creator><creator>Bell, Peter</creator><creator>Marchadier, Dawn</creator><creator>Wilson, Aisha</creator><creator>Cromley, Debra</creator><creator>Redon, Valeska</creator><creator>Yu, Hongwei</creator><creator>Wilson, James M</creator><creator>Rader, Daniel J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20101019</creationdate><title>Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis</title><author>Kassim, Sadik H ; Li, Hui ; Vandenberghe, Luk H ; Hinderer, Christian ; Bell, Peter ; Marchadier, Dawn ; Wilson, Aisha ; Cromley, Debra ; Redon, Valeska ; Yu, Hongwei ; Wilson, James M ; Rader, Daniel J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c789t-1e59b20139d988688a2a60c01462cd0b3743a2f72e9009f29d6a725f86b080f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adeno-associated virus</topic><topic>Adolescence</topic><topic>Adolescents</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antigens</topic><topic>Arteriosclerosis</topic><topic>Atherogenesis</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis - therapy</topic><topic>Base Sequence</topic><topic>Blood cholesterol</topic><topic>Cardiovascular Disorders</topic><topic>Children</topic><topic>Cholesterol</topic><topic>Clinical aspects</topic><topic>Computer simulation</topic><topic>Disease Models, Animal</topic><topic>DNA Primers</topic><topic>Epidemiology</topic><topic>Gastroenterology and Hepatology/Hepatology</topic><topic>Gene therapy</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic Therapy</topic><topic>Genetics and Genomics/Gene Therapy</topic><topic>Genetics and Genomics/Genetics of Disease</topic><topic>Genomes</topic><topic>Hemophilia</topic><topic>High density lipoprotein</topic><topic>House mouse</topic><topic>Humans</topic><topic>Hypercholesterolemia</topic><topic>Hyperlipoproteinemia Type II - therapy</topic><topic>Immunohistochemistry</topic><topic>Intravenous administration</topic><topic>Laboratories</topic><topic>Lesions</topic><topic>Low density lipoprotein receptors</topic><topic>Low density lipoproteins</topic><topic>Lymphocytes</topic><topic>Male</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mutation</topic><topic>Pathology</topic><topic>Receptor density</topic><topic>Receptors, LDL - genetics</topic><topic>Regression analysis</topic><topic>Translation (Genetics)</topic><topic>Vectors (Biology)</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kassim, Sadik H</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Vandenberghe, Luk H</creatorcontrib><creatorcontrib>Hinderer, Christian</creatorcontrib><creatorcontrib>Bell, Peter</creatorcontrib><creatorcontrib>Marchadier, Dawn</creatorcontrib><creatorcontrib>Wilson, Aisha</creatorcontrib><creatorcontrib>Cromley, Debra</creatorcontrib><creatorcontrib>Redon, Valeska</creatorcontrib><creatorcontrib>Yu, Hongwei</creatorcontrib><creatorcontrib>Wilson, James M</creatorcontrib><creatorcontrib>Rader, Daniel J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection (ProQuest)</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kassim, Sadik H</au><au>Li, Hui</au><au>Vandenberghe, Luk H</au><au>Hinderer, Christian</au><au>Bell, Peter</au><au>Marchadier, Dawn</au><au>Wilson, Aisha</au><au>Cromley, Debra</au><au>Redon, Valeska</au><au>Yu, Hongwei</au><au>Wilson, James M</au><au>Rader, Daniel J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2010-10-19</date><risdate>2010</risdate><volume>5</volume><issue>10</issue><spage>e13424</spage><epage>e13424</epage><pages>e13424-e13424</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20976059</pmid><doi>10.1371/journal.pone.0013424</doi><tpages>e13424</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2010-10, Vol.5 (10), p.e13424-e13424 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1292194354 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adeno-associated virus Adolescence Adolescents Analysis Animals Antigens Arteriosclerosis Atherogenesis Atherosclerosis Atherosclerosis - therapy Base Sequence Blood cholesterol Cardiovascular Disorders Children Cholesterol Clinical aspects Computer simulation Disease Models, Animal DNA Primers Epidemiology Gastroenterology and Hepatology/Hepatology Gene therapy Genes Genetic aspects Genetic Therapy Genetics and Genomics/Gene Therapy Genetics and Genomics/Genetics of Disease Genomes Hemophilia High density lipoprotein House mouse Humans Hypercholesterolemia Hyperlipoproteinemia Type II - therapy Immunohistochemistry Intravenous administration Laboratories Lesions Low density lipoprotein receptors Low density lipoproteins Lymphocytes Male Medicine Metabolism Mice Mice, Inbred C57BL Mutation Pathology Receptor density Receptors, LDL - genetics Regression analysis Translation (Genetics) Vectors (Biology) Viruses |
| title | Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T00%3A16%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gene%20therapy%20in%20a%20humanized%20mouse%20model%20of%20familial%20hypercholesterolemia%20leads%20to%20marked%20regression%20of%20atherosclerosis&rft.jtitle=PloS%20one&rft.au=Kassim,%20Sadik%20H&rft.date=2010-10-19&rft.volume=5&rft.issue=10&rft.spage=e13424&rft.epage=e13424&rft.pages=e13424-e13424&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0013424&rft_dat=%3Cgale_plos_%3EA473846713%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1292194354&rft_id=info:pmid/20976059&rft_galeid=A473846713&rft_doaj_id=oai_doaj_org_article_e79587d53a7b4820b632c5dfd2a0f483&rfr_iscdi=true |