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Pulmonary delivery of adenovirus vector formulated with dexamethasone–spermine facilitates homologous vector re-administration

Gene Therapy volume 14, pages 1594–1604 (2007)Cite this article

Abstract

Gene transfer to lung has been hindered by inflammatory and immunological responses activated to the gene-transfer agent or transgene products. In prior work, adenovirus vector delivered to the lung with the cationic glucocorticoid, dexamethasone–spermine (DS) had improved targeting to conducting airway epithelium and reduced cellular infiltration. In this study, the effect of formulation on homologous adenovirus vector re-administration was studied in C57Bl/6 mice. Formulation of an adenovirus vector expressing LacZ with DS/dioleoylphosphatidylethanolamine (DOPE) delivered at day 0 allowed re-administration of adenovirus vector expressing alkaline phosphatase at day 21. Formulation with 3β [N-(N′, N′-dimethylaminoethane) carbamoy] cholesterol (DC-Chol) DC-cholesterol (DC-Chol))/DOPE or dexamethasone in the first dosing at day 0 resulted in moderate alkaline phosphatase expression at day 24. Neutralizing antibodies against adenovirus vector in serum at day 28 were greatly reduced by all three formulations in mice receiving a single dose of adenovirus at day 0. Also, homologous adenovirus vector re-administration at day 14 produced less neutralizing antibody at day 28 when adenovirus was formulated with DS/DOPE at day 0. The use of DS/DOPE at day 0 dramatically reduced CD4 and CD8 T-cell infiltration in mice receiving adenovirus at day 0 followed by vector re-administration at day 14. Transgene-specific T-cell activation was markedly reduced by the DC-Chol/DOPE formulation. Overall, DS/DOPE) facilitated homologous vector re-administration through a combination of liposomal and glucocorticoid mechanisms.

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Acknowledgements

This work was supported by National Institutes of Health Grant HL66565 and Cystic Fibrosis Foundation Grants D01IO and 5886, and P30 (DK047757). We thank Deirdre McMenamin and Regina Munden for invaluable assistance with animal work. Peter Bell and Di Wu are also gratefully acknowledged for expert morphology work and Roberto Calcedo, Jim Miller and Judith Franco are thanked for performing NAB assays. Finally, we express our thanks to the Penn Vector Core for providing AdV vectors.

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  1. A R Price and M P Limberis: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Bioengineering, Institute for Medicine and Engineering, Vagelos Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA

    A R Price & S L Diamond

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    M P Limberis & J M Wilson

  3. Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, Vagelos Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA

    S L Diamond

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  1. A R Price
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Correspondence to S L Diamond.

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Price, A., Limberis, M., Wilson, J. et al. Pulmonary delivery of adenovirus vector formulated with dexamethasone–spermine facilitates homologous vector re-administration. Gene Ther 14, 1594–1604 (2007). https://doi.org/10.1038/sj.gt.3303031

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