Apolipoprotein B Knockdown by AAV-delivered shRNA Lowers Plasma Cholesterol in Mice
| العنوان: | Apolipoprotein B Knockdown by AAV-delivered shRNA Lowers Plasma Cholesterol in Mice |
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| المؤلفون: | Florie Borel, Pavlina Konstantinova, Tita Ritsema, Sander J. H. van Deventer, Richard van Logtenstein, Harald Petry, Piotr Maczuga, Annemart Koornneef, Bas Blits |
| المساهمون: | Other departments |
| المصدر: | Molecular Therapy, 19(4), 731-740 Molecular therapy, 19(4), 731-740. Nature Publishing Group |
| بيانات النشر: | Nature Publishing Group, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Male, adenoassociated virus vectors in-vivo delivery double-stranded-rna messenger-rna ldl cholesterol gene-therapy liver transduction nonhuman-primates sirna delivery expression, Apolipoprotein B, Genetic enhancement, Blotting, Western, Genetic Vectors, Biology, Cell Line, Small hairpin RNA, chemistry.chemical_compound, Mice, In vivo, RNA interference, Cell Line, Tumor, Drug Discovery, Genetics, Animals, Humans, RNA, Small Interfering, Molecular Biology, Apolipoproteins B, Pharmacology, Messenger RNA, Gene knockdown, Cholesterol, Reverse Transcriptase Polymerase Chain Reaction, Dependovirus, Molecular biology, Mice, Inbred C57BL, chemistry, biology.protein, Molecular Medicine, lipids (amino acids, peptides, and proteins), Original Article |
| الوصف: | Serum low-density lipoprotein cholesterol (LDL-C) levels are proportionate to the risk of atherosclerotic cardiovascular disease. In order to reduce serum total cholesterol and LDL-C levels in mice, RNA interference (RNAi) was used to inhibit expression of the structural protein of LDL-C, apolipoprotein B100 (ApoB). We developed and screened 19 short hairpin RNAs (shRNAs) targeting conserved sequences in human, mouse, and macaque ApoB mRNAs (shApoB) and subsequently narrowed our focus to one candidate for in vivo testing. Self-complementary adeno-associated virus serotype 8 (scAAV8) was used for long-term transduction of murine liver with shApoB. A strong dose-dependent knockdown of ApoB mRNA and protein was observed, which correlated with a reduction in total cholesterol levels, without obvious signs of toxicity. Furthermore, shApoB was found to specifically reduce LDL-C in diet-induced dyslipidemic mice, whereas high-density lipoprotein cholesterol (HDL-C) remained unaffected. Finally, elevated lipid accumulation was shown in murine liver transduced with shApoB, a known phenotypic side effect of lowering ApoB levels. These results demonstrate a robust dose-dependent knockdown of ApoB by AAV-delivered shRNA in murine liver, thus providing an excellent candidate for development of RNAi-based gene therapy for the treatment of hypercholesterolemia. |
| اللغة: | English |
| تدمد: | 1525-0016 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::827ac9dbeaeb303ed9d1e8cccf4a173aTest https://europepmc.org/articles/PMC3070114Test/ |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....827ac9dbeaeb303ed9d1e8cccf4a173a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15250016 |
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