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Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration.

TitleInnate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration.
Publication TypeJournal Article
Year of Publication1997
AuthorsWorgall S, Wolff G, Falck-Pedersen E, Crystal RG
JournalHum Gene Ther
Volume8
Issue1
Pagination37-44
Date Published1997 Jan 01
ISSN1043-0342
KeywordsAdenoviridae, Animals, beta-Galactosidase, Blotting, Southern, DNA Probes, DNA, Viral, Gene Expression Regulation, Gene Transfer Techniques, Genetic Vectors, Immunity, Liver, Mice, Mice, Inbred BALB C, Mice, Nude
Abstract

To evaluate the contribution of the innate immune component of host defense in clearing the genome of adenovirus (Ad) vectors following in vivo administration, the Ad vectors AdCMV.beta gal (expressing beta-galactosidase) or AdCMV.Null (expressing no gene) were administered intravenously to immunocompetent or immunodeficient mice, and the amount of vector genome was quantified in the liver. Strikingly, 90% of vector DNA was eliminated within 24 hr. There was no increase in vector DNA in other tissues over this period, suggesting that rapid clearance of vector genome resulted from local degradation. After 24 hr, vector elimination was slow, with only 9% of the initial amount of vector genome cleared over the subsequent 3 weeks. Importantly, early phase (0-24 hr) elimination of vector DNA was independent of the transgene and similar in immunocompetent and nude animals. These observations suggest two phases of Ad vector elimination: a previously recognized late, immune-related elimination, and the early, innate immune elimination described in the present study. The early phase of vector loss is, by far, the dominant mechanism, an observation that has implications in developing strategies to maintain persistent expression of the newly transferred gene following in vivo gene therapy.

DOI10.1089/hum.1997.8.1-37
Alternate JournalHum Gene Ther
PubMed ID8989993
Grant ListP01 HL51746-03 / HL / NHLBI NIH HHS / United States

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