Transient pretreatment with glucocorticoid ablates innate toxicity of systemically delivered adenoviral vectors without reducing efficacy

Sergey S. Seregin, Daniel M. Appledorn, Aaron J. McBride, Nathan Schuldt, Yasser A. Aldhamen, Tyler Voss, Junping Wei, Matthew Bujold, William Nance, Sarah Godbehere, Andrea Amalfitano

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

More than 300 human clinical trials utilize recombinant adenoviruses (rAds) as a gene transfer vector, confirming that rAds continue to be of high clinical interest. A primary weakness of rAds is their known propensity to trigger an innate, proinflammatory immune response rapidly after high-dose, systemic administration. In this study, we investigated what affects that pre-emptive treatment with anti-inflammatory glucocorticoids might have upon Ad vector-triggered inflammatory immune responses. We found that a simple pretreatment regimen with Dexamethasone (DEX) can significantly reduce most Ad-induced innate immune responses. DEX prevented rAd induction of systemic cytokine/ chemokine releases in a dose-dependent fashion, with higher dosages preventing rAd induction of acute thrombocytopenia, endothelial cell activation, proinflammatory gene induction, and leukocyte infiltration into transduced organs. Transient glucocorticoid pretreatment also significantly reduced rAd-induced adaptive immune responses, including a decreased induction of Ad-neutralizing antibodies (NAbs). Importantly, use of DEX did not reduce the efficacy of rAd-mediated gene transduction nor rAd-derived transgene expression. Our results demonstrate that a simple, pre-emptive and transient glucocorticoid pretreatment is a viable approach to reduce rAd-associated acute toxicities that currently limit the use of Ad vectors in systemic clinical applications.

Original languageEnglish (US)
Pages (from-to)685-696
Number of pages12
JournalMolecular Therapy
Volume17
Issue number4
DOIs
StatePublished - 2009
Externally publishedYes

Bibliographical note

Funding Information:
We thank Michigan State University Laboratory Animal support facility for their assistance in the humane care and maintenance of the animals utilized in this work. S.S.S. was supported by American Heart Association Midwest Affiliate Fellowship 0815660G. A.A. was supported by the National Institutes of Health grants RO1DK-069884, P01 CA078673, the MSU Foundation, as well as the Osteopathic Heritage Foundation.

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

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