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Modulation of TNFα, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors

Gene Therapy volume 13, pages 1272–1280 (2006)Cite this article

Abstract

Understanding the determinants of the host innate immune response to systemic administration of adenoviral (Ad) vectors is critical for clinical gene therapy. Acute toxicity occurs within minutes to hours after vector administration and is characterized by activation of innate immune responses. Our data indicate that in mice, indicators of vector toxicity include elevations of cytokine levels, liver transaminase levels and thrombocytopenia. To discern potential targets for blunting this host response, we evaluated genetic factors in the host response to systemically administered first-generation Ad vectors (FGV) and helper-dependent Ad vectors (HDV) containing β-galactosidase expression cassettes. A preliminary screen for modulation of vector-induced thrombocytopenia revealed no role for interferon-γ, mast cells or perforin. However, vector-induced thrombocytopenia and interleukin 6 (IL-6) expression are less evident in tumor necrosis factor alpha (TNFα)-deficient mice. Moreover, we also demonstrated that TNFα blockade via antibody or huTNFR:Fc pretreatment attenuates both thrombocytopenia (>40% increase in platelet count) and IL-6 expression (>80% reduction) without affecting interleukin 12 , liver enzymes, hematological indices or vector transduction in a murine model. Our data indicate that the use of HDV, in combination with clinically approved TNFα immunomodulation, may represent an approach for improving the therapeutic index of Ad gene therapy for human clinical trials.

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Abbreviations

Ad:

adenovirus

FGV:

first-generation adenoviral vector

HDV:

helper-dependent adenoviral vector

IL-6:

interleukin 6

IL-12:

interleukin 12

TNFα:

tumor necrosis factor alpha

i.v.:

intravenous

i.p.:

intraperitoneal

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Acknowledgements

BL was supported by NIH DK56787, NIH DK58338, NIH HD24046 and PN was supported by P50 HL59314. LP was supported by Telethon Grant GGP04039. We gratefully acknowledge Dorene M Rudman of the NIDDK-sponsored Gulf Coast Digestive Disease Center Morphology Core Laboratory (P30 DK56338) at Texas Children's Hospital (Houston, TX) for tissue sectioning, hematoxylin and eosin staining and X-gal staining. We also acknowledge Ovida Hortenstine at the Pathology Laboratory of the Center for Comparative Medicine (Baylor College of Medicine, Houston, TX) for all CBC and transaminase readings.

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Author notes

  1. V P Mane and G Toietta: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    V P Mane, G Toietta, W M McCormack, C Clarke, D Palmer, P Ng & B Lee

  2. Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    M J Finegold

  3. Department of Medicine-Thrombosis, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    I Conde & J Lopez

  4. Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    B Lee

  5. Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE-Biotecnologie Avanzate, Università degli Studi di Napoli Federico II, Naples, Italy

    L Pastore

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  1. V P Mane
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Correspondence to B Lee.

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This article is dedicated to the memory of our colleague and friend WM McCormack Jr (12 August 1965 – 29 July 2005).

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Mane, V., Toietta, G., McCormack, W. et al. Modulation of TNFα, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors. Gene Ther 13, 1272–1280 (2006). https://doi.org/10.1038/sj.gt.3302792

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