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Sustained expression of human apo A-I following adenoviral gene transfer in mice

Gene Therapy volume 8, pages 121–127 (2001)Cite this article

Abstract

Elevation of HDL cholesterol, following adenoviral apolipoprotein A-I (apo A-I) gene transfer, may delay or revert ischemic cardiovascular disease, provided transgene expression is persistent. The choice of promoter may have significant impact on persistence of transgene expression. Human apo A-I expression was compared after adenoviral gene transfer with a cytomegalovirus promoter (CMV) driven construct (AdCMV/A-I.gA-I) and with a construct (AdA-I.gA-I.4xapoE) containing the endogenous 256 bp apo A-I promoter (A-I), the genomic human apo A-I DNA (gA-I) and 4 human apo E enhancers (4xapoE) in three different mouse strains: C57BL/6, Balb/c and Fvb. After gene transfer with 5 × 108 p.f.u. of AdCMV/A-I.gA-I, human apo A-I expression was observed for 35 days in C57BL/6 mice, but declined below 1 mg/dl within 14 days both in Balb/c and Fvb mice, due to a strong humoral immune response against human apo A-I. In contrast, after transfer with AdA-I.gA-I.4xapoE, human apo A-I expression persisted for 6 months in all three strains and no antibodies against human apo A-I occurred in Fvb or Balb/c mice. Human apo A-I transgene DNA level 35 days after transfer with AdA-I.gA-I.4xapoE was 4.6- to 5.5-fold higher than with AdCMV/A-I.gA-I. CMV promoter attenuation occurred in all three strains, but promoter attenuation was not observed in any strain after transfer with AdA-I.gA-I.4xapoE. In conclusion, gene transfer with AdA-I.gA-I.4xapoE is associated with absence of an immune response against human apo A-I, improved transgene DNA persistence and absence of promoter shut-off, resulting in human apo A-I expression for up to 6 months in three different mouse strains. Possibly, the absence of human apo A-I expression in antigen-presenting cells with the liver-specific apo A-I promoter containing construct abrogated the immune response against human apo A-I in Balb/c and Fvb mice.

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Acknowledgements

Bart De Geest is a Postdoctoral Fellow of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. Sophie Van Linthout is a Research Assistant of the Instituut voor Wetenschappelijk en Technisch Onderzoek-Vlaanderen. We thank Z Zhang for excellent technical assistance.

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  1. Center for Molecular and Vascular Biology, University of Leuven, Belgium

    B De Geest, S Van Linthout & D Collen

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  1. B De Geest
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  2. S Van Linthout
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  3. D Collen
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De Geest, B., Van Linthout, S. & Collen, D. Sustained expression of human apo A-I following adenoviral gene transfer in mice. Gene Ther 8, 121–127 (2001). https://doi.org/10.1038/sj.gt.3301374

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