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Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease

Gene Therapy volume 11, pages 431–438 (2004)Cite this article

Abstract

When adenovirus vectors are injected intravenously, most of the virions are quickly taken up by the reticuloendothelial system, primarily by the liver macrophages known as Kupffer cells. However, little is known about the behavior of adenovirus vectors when there is pre-existing liver disease. To study this, we examined the biodistribution of intravenously injected vector in a rat model of cirrhosis induced by bile duct ligation. Using quantitative PCR and fluorescently tagged adenovirus vectors, we observed a significant reduction in vector uptake by the cirrhotic liver and increased accumulation in the lungs. Immunocytochemistry and electron microscopy demonstrated that this was due to changes in the reticuloendothelial system, with the vector being taken up by large numbers of pulmonary intravascular macrophages in the lungs of cirrhotic rats. Interestingly, expression of vector-encoded luciferase was significantly reduced in the livers of cirrhotic rats, but was not increased in the lungs. These data demonstrate that the biodistribution of adenovirus vectors in rats is altered by cirrhosis, which suggests the possibility that these vectors might behave unexpectedly in patients with pre-existing liver conditions, particularly since pulmonary reticuloendothelial changes are known to occur in human disease.

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Acknowledgements

We appreciate the expert technical assistance of Marilyn Lundquist in the preparation of material for electron microscopy. We thank Anne Pilaro, Steve Rubin, and Günter Cichon for critical reviews of the manuscript.

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Authors and Affiliations

  1. Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA

    JS Smith, J Tian & AP Byrnes

  2. Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA

    J Muller

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Smith, J., Tian, J., Muller, J. et al. Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease. Gene Ther 11, 431–438 (2004). https://doi.org/10.1038/sj.gt.3302149

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