| Generation of a Kupffer Cell-evading Adenovirus for Systemic and Liver-directed Gene Transfer. | |
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MedLine Citation:
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PMID: 21505422 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vector, Ad5/6 mediated higher luciferase and factor IX transgene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies. |
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Authors:
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Reeti Khare; Shannon M May; Francesco Vetrini; Eric A Weaver; Donna Palmer; Amanda Rosewell; Nathan Grove; Philip Ng; Michael A Barry |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-19 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: - ISSN: 1525-0024 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Virology and Gene Therapy Program, Mayo Graduate School, Rochester, Minnesota, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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