Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

K. Oka, L. M. Belalcazar, C. Dieker, E. A. Nour, P. Nuno-Gonzalez, A. Paul, S. Cormier, J. K. Shin, M. Finegold, L. Chan

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

We examined the efficacy and host response to the adenovirus (Ad)-mediated delivery of human apolipoprotein A-I (APOA1) gene to the liver of APOA1-/- mice. Administration of a first-generation vector (FGAd-AI) resulted in a transient appearance of APOA1 in plasma and induced an anti-APOA1 antibody titer, whereas treatment with a helper-dependent vector (HDAd-AI) resulted in sustained APOA1 expression without inducing an antibody titer. With these results, we studied the effects of FGAd vectors on APOAI expression by HDAd-AI vector. Co-treatment with an FGAd vector inhibited HDAd-AI- mediated APOA1 expression independent of transgene cassettes, but only FGAd-AI induced a humoral response. Furthermore, APOA1 mRNA levels in mice co-treated with FGAd vectors were much lower than those expected from the vector copy number, suggesting that DNA of FGAd vectors interferes with the HDAd-AI vector's APOA1 promoter. A single treatment with an HDAd-AI vector produced a supraphysiological plasma APOA1 level that gradually declined to about half the normal human level over the course of 2 years, associated with a plasma cholesterol level that is persistently higher than that in controls. This investigation provides the proof of principle that liver-directed HDAd gene delivery is effective for the long-term phenotypic correction of monogenic hypoalphalipoproteinemia.

Original languageEnglish (US)
Pages (from-to)191-202
Number of pages12
JournalGene Therapy
Volume14
Issue number3
DOIs
StatePublished - Feb 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Oka, K., Belalcazar, L. M., Dieker, C., Nour, E. A., Nuno-Gonzalez, P., Paul, A., Cormier, S., Shin, J. K., Finegold, M., & Chan, L. (2007). Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector. Gene Therapy, 14(3), 191-202. https://doi.org/10.1038/sj.gt.3302819