Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein
Cardiovascular disease is the leading worldwide cause of death. Apolipoprotein E (ApoE) is a 34-kDa circulating glycoprotein, secreted by the liver and macrophages with pleiotropic antiatherogenic functions and hence a candidate to treat hypercholesterolaemia and atherosclerosis. Here, we describe a...
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| Format: | Article |
| Language: | English |
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Wiley
2012-01-01
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| Series: | Cardiology Research and Practice |
| Online Access: | http://dx.doi.org/10.1155/2012/148796 |
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| author | Ioannis Papaioannou J. Paul Simons James S. Owen |
| author_facet | Ioannis Papaioannou J. Paul Simons James S. Owen |
| author_sort | Ioannis Papaioannou |
| collection | DOAJ |
| description | Cardiovascular disease is the leading worldwide cause of death. Apolipoprotein E (ApoE) is a 34-kDa circulating glycoprotein, secreted by the liver and macrophages with pleiotropic antiatherogenic functions and hence a candidate to treat hypercholesterolaemia and atherosclerosis. Here, we describe atheroprotective properties of ApoE, though also potential proatherogenic actions, and the prevalence of dysfunctional isoforms, outline conventional gene transfer strategies, and then focus on gene correction therapeutics that can repair defective APOE alleles. In particular, we discuss the possibility and potential benefit of applying in combination two technical advances to repair aberrant APOE genes: (i) an engineered endonuclease to introduce a double-strand break (DSB) in exon 4, which contains the common, but dysfunctional, ε2 and ε4 alleles; (ii) an efficient and selectable template for homologous recombination (HR) repair, namely, an adeno-associated viral (AAV) vector, which harbours wild-type APOE sequence. This technology is applicable ex vivo, for example to target haematopoietic or induced pluripotent stem cells, and also for in vivo hepatic gene targeting. It is to be hoped that such emerging technology will eventually translate to patient therapy to reduce CVD risk. |
| format | Article |
| id | doaj-art-11323930837b4986b3e3ca5bdac8b27d |
| institution | Kabale University |
| issn | 2090-8016 2090-0597 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cardiology Research and Practice |
| spelling | doaj-art-11323930837b4986b3e3ca5bdac8b27d2025-02-03T05:51:36ZengWileyCardiology Research and Practice2090-80162090-05972012-01-01201210.1155/2012/148796148796Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 ProteinIoannis Papaioannou0J. Paul Simons1James S. Owen2Division of Medicine, UCL Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UKDivision of Medicine, UCL Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UKDivision of Medicine, UCL Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UKCardiovascular disease is the leading worldwide cause of death. Apolipoprotein E (ApoE) is a 34-kDa circulating glycoprotein, secreted by the liver and macrophages with pleiotropic antiatherogenic functions and hence a candidate to treat hypercholesterolaemia and atherosclerosis. Here, we describe atheroprotective properties of ApoE, though also potential proatherogenic actions, and the prevalence of dysfunctional isoforms, outline conventional gene transfer strategies, and then focus on gene correction therapeutics that can repair defective APOE alleles. In particular, we discuss the possibility and potential benefit of applying in combination two technical advances to repair aberrant APOE genes: (i) an engineered endonuclease to introduce a double-strand break (DSB) in exon 4, which contains the common, but dysfunctional, ε2 and ε4 alleles; (ii) an efficient and selectable template for homologous recombination (HR) repair, namely, an adeno-associated viral (AAV) vector, which harbours wild-type APOE sequence. This technology is applicable ex vivo, for example to target haematopoietic or induced pluripotent stem cells, and also for in vivo hepatic gene targeting. It is to be hoped that such emerging technology will eventually translate to patient therapy to reduce CVD risk.http://dx.doi.org/10.1155/2012/148796 |
| spellingShingle | Ioannis Papaioannou J. Paul Simons James S. Owen Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein Cardiology Research and Practice |
| title | Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein |
| title_full | Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein |
| title_fullStr | Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein |
| title_full_unstemmed | Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein |
| title_short | Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein |
| title_sort | targeted in situ gene correction of dysfunctional apoe alleles to produce atheroprotective plasma apoe3 protein |
| url | http://dx.doi.org/10.1155/2012/148796 |
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