Effect of the E4 region on the persistence of transgene expression from adenovirus vectors

Donna Armentano; Joseph Zabner; Carol Sacks; Cathleen C Sookdeo; Michael P Smith; Judith A St. George; Samuel C Wadsworth; Alan E Smith; Richard J Gregory

doi:10.1128/jvi.71.3.2408-2416.1997

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Effect of the E4 region on the persistence of transgene expression from adenovirus vectors

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Effect of the E4 region on the persistence of transgene expression from adenovirus vectors

Donna Armentano, Joseph Zabner, Carol Sacks, Cathleen C Sookdeo, Michael P Smith, Judith A St. George, Samuel C Wadsworth, Alan E Smith and Richard J Gregory

Journal of virology, Vol.71(3), pp.2408-2416

03/1997

DOI: 10.1128/jvi.71.3.2408-2416.1997

PMCID: PMC191351

PMID: 9032378

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Abstract

The utility of adenovirus vectors for gene therapy is limited by the transience of expression that has been observed in various in vivo models. Immunological responses to viral targets can eliminate transduced cells and cause the loss of transgene expression. We previously described the characterization of an E4 modified adenovirus, Ad2E4ORF6, which is replication defective in cotton rats. We reasoned that gene transfer vectors based on Ad2E4ORF6 would have a reduced potential for viral gene expression in vivo which might be beneficial for achieving persistence of transgene expression. E1 replacement vectors expressing the cystic fibrosis transmembrane regulator or beta-galactosidase were constructed as series of vectors that differed with respect to the E4 region. Vectors containing a wild-type E4 region, E4 open reading frame 6, or a complete E4 deletion were compared in the lungs of BALB/c mice for persistence of expression. Results obtained with nude mice indicate that nonimmunological factors have a major influence on the longevity of transgene expression. Expression was transient from the E1a promoter with all vectors but persisted from the cytomegalovirus promoter only with a vector containing a wild-type E4 region. Transience of expression did not correlate with the disappearance of vector DNA, suggesting that promoter down-regulation may be involved. Coinfection studies indicate an E4 product(s) could be supplied in trans to allow persistent expression from the cytomegalovirus promoter. In summary, the choice of promoter is important for achieving persistence of expression; in addition, some promoters are highly influenced by the context of the vector backbone.

Details

Title: Subtitle: Effect of the E4 region on the persistence of transgene expression from adenovirus vectors
Creators: Donna Armentano - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Joseph Zabner - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Carol Sacks - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Cathleen C Sookdeo - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Michael P Smith - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Judith A St. George - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Samuel C Wadsworth - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Alan E Smith - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Richard J Gregory - Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA
Resource Type: Journal article
Publication Details: Journal of virology, Vol.71(3), pp.2408-2416
DOI: 10.1128/jvi.71.3.2408-2416.1997
PMID: 9032378
PMCID: PMC191351
ISSN: 0022-538X
eISSN: 1098-5514
Language: English
Date published: 03/1997
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984094494402771

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