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

Gene Therapy volume 14, pages 191–202 (2007)Cite this article

A Corrigendum to this article was published on 03 May 2007

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.

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Acknowledgements

This work was supported by HL59314 and HL73144. A Paul was supported by the grant from American Heart Association (0535118N). We thank A Beaudet for valuable discussion; S Kochanek and G Shiedner for providing 293Cre66 cells; J Smith for APOE gene; F Graham for providing helper virus; Merck & Co. for providing reagents developed by F Graham.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

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

  2. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    K Oka & L Chan

  3. Department of Neurology, Baylor College of Medicine, Houston, TX, USA

    K Oka

  4. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    M Finegold

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  1. K Oka
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Correspondence to K Oka.

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Oka, K., Belalcazar, L., Dieker, C. et al. Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector. Gene Ther 14, 191–202 (2007). https://doi.org/10.1038/sj.gt.3302819

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