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

Nuria 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 journalArticle

356 Citations (Scopus)

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
Externally publishedYes

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Papio
Transgenes
Liver
Viral Proteins
Genes
Poisons
Adenoviridae
Viruses
Serogroup

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. / Morral, Nuria; O'Neal, Wanda; Rice, Karen; Leland, Michele; Kaplan, Johanne; Piedra, Pedro A.; Zhou, Heshan; Parks, Robin J.; Velji, Rizwan; Aguilar-Córdova, Estuardo; Wadsworth, Samuel; Graham, Frank L.; Kochanek, Stefan; Dee Carey, K.; Beaudet, Arthur L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 22, 26.10.1999, p. 12816-12821.

Research output: Contribution to journalArticle

Morral, N, O'Neal, W, Rice, K, Leland, M, Kaplan, J, Piedra, PA, Zhou, H, Parks, RJ, Velji, R, Aguilar-Córdova, E, Wadsworth, S, Graham, FL, Kochanek, S, Dee Carey, K & Beaudet, AL 1999, 'Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 22, pp. 12816-12821. https://doi.org/10.1073/pnas.96.22.12816
Morral, Nuria ; O'Neal, Wanda ; Rice, Karen ; Leland, Michele ; Kaplan, Johanne ; Piedra, Pedro A. ; Zhou, Heshan ; Parks, Robin J. ; Velji, Rizwan ; Aguilar-Córdova, Estuardo ; Wadsworth, Samuel ; Graham, Frank L. ; Kochanek, Stefan ; Dee Carey, K. ; Beaudet, Arthur L. / Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 22. pp. 12816-12821.
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AU - Leland, Michele

AU - Kaplan, Johanne

AU - Piedra, Pedro A.

AU - Zhou, Heshan

AU - Parks, Robin J.

AU - Velji, Rizwan

AU - Aguilar-Córdova, Estuardo

AU - Wadsworth, Samuel

AU - Graham, Frank L.

AU - Kochanek, Stefan

AU - Dee Carey, K.

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