Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons

Núria Morral, Wanda O'Neal, Karen Rice, Michele Leland, Johanne Kaplan, Pedro A. Piedra, Heshan Zhou, Robin J. Parks, Rizwan Velji, Estuardo Aguilar-Córdova, Samuel Wadsworth, Frank L. Graham, Stefan Kochanek, K. Dee Carey, Arthur L. Beaudet

Research output: Contribution to journalArticlepeer-review

366 Scopus citations

Abstract

The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human α1-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report, we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first- generation vectors expressing hAAT. Transgene expression was limited to approximately 3-5 months with the first-generation vectors. In contrast, administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of vectors of different serotypes.

Original languageEnglish (US)
Pages (from-to)12816-12821
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number22
DOIs
StatePublished - Oct 26 1999

ASJC Scopus subject areas

  • General

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