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Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naïve and pre-immunized mice

Gene Therapy volume 12, pages 427–436 (2005)Cite this article

Abstract

Toxicity associated with in vivo administration of adenovirus (Ad) vectors has been linked to activation of both innate and adaptive immune responses. Pre-existing immunity to the prevalent Ad serotypes, acquired by the majority of the human population as a result of natural infections, has the potential to modulate vector efficacy and safety. Previously, we evaluated some aspects of toxicity from systemic Ad vector in vector-naïve and pre-immunized rhesus monkeys. In this report, we summarize data from several studies analyzing toxic effects from systemically administered E1/E3-deleted Ad vector in vector-naïve and pre-immunized C57BL/6 mice. Our results indicate that pre-immunization can be associated with increased mortality shortly after systemic administration of Ad. Transient leukopenia and thrombocytopenia were observed early post vector infusion in both vector-naïve and pre-immunized animals. Pre-exposure to the vector did not prevent induction of pro-inflammatory cytokines; however, pre-immunized mice showed less tissue toxicity. Growth of bone marrow myeloid and erythroid progenitors was transiently inhibited in pre-immunized animals, but only the myeloid progenitors were affected in vector-naïve animals. In summary, pre-existing immunity to Ad vector substantially modifies host immune responses to systemic Ad vector.

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Acknowledgements

We are grateful to the technical personnel of Animal Model, Vector, Cell Morphology and QC Cores of the University of Pennsylvania for assistance. This work was supported by the NIH (NIDDK P30 DK47757-09, NHLBI P01 HL59407-03), the Juvenile Diabetes Research Foundation, the Cystic Fibrosis Foundation and GlaxoSmithKline Pharmaceuticals. James M Wilson is an inventor on patents licensed to various commercial entities.

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  1. A N Varnavski

    Present address: Antigenics, Inc., Lexington, MA, 02421, USA

Authors and Affiliations

  1. Gene Therapy Program at the University of Pennsylvania School of Medicine, Department of Medicine, Division of Medical Genetics, Philadelphia, PA, USA

    A N Varnavski, R Calcedo, M Bove, G Gao & J M Wilson

  2. The Wistar Institute, Philadelphia, PA, USA

    A N Varnavski, R Calcedo, M Bove, G Gao & J M Wilson

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  1. A N Varnavski
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Varnavski, A., Calcedo, R., Bove, M. et al. Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naïve and pre-immunized mice. Gene Ther 12, 427–436 (2005). https://doi.org/10.1038/sj.gt.3302347

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