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Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts

Gene Therapy volume 14, pages 1613–1622 (2007)Cite this article

Abstract

Sequestration of tumor necrosis factor-α (TNFα) by TNF-receptor immunoglobulin G (IgG)-Fc fusion proteins can limit heart failure progression in rodent models. In this study we directly injected an adeno-associated viruses (AAV)-2 construct encoding a human TNF receptor II IgG-Fc fusion protein (AAV-TNFRII-Fc) into healthy baboon hearts and assessed virally encoded gene expression and clinical response. Adult baboons received direct cardiac injections of AAV-TNFRII-Fc (∼5 × 1012 viral/genomes/baboon) or an equivalent dose of AAV-2 empty capsids, and were analyzed after 5 or 12 weeks. Viral genomes were restricted to the myocardium, and routine analyses (blood cell counts, clinical chemistries) remained unremarkable. Echocardiograms were unchanged but electrocardiograms revealed marked ST- and T-wave changes consistent with myocarditis only in baboons receiving AAV-TNFRII-Fc. TNFRII serum levels peaked at ∼3 times the baseline levels at 1–2 weeks postinjection and subsequently declined to baseline levels. TNFRII-Fc protein and transcripts were detected in the heart at harvest. After AAV injection, anti-AAV-2 antibody levels increased in all baboons, while anti-TNFRII-Fc could not be detected. Baboons that received AAV-TNFRII-Fc developed myocardial infiltrates including CD8+ cells. Thus, a cellular immune response to cardiac delivery of AAV encoding foreign proteins may be an important consideration for AAV-based cardiac gene therapy.

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Acknowledgements

We thank Bonnie Lemster, Tjendimin Tjandrawan, Jennifer Rager, David Meleason and Michael Murphey-Corb for their contributions in animal procedures and analyses, and Paul Robbins for plasmids encoding TNFRII-Fc. The work was supported by NIH grant U01HL66949.

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Author notes

  1. C F McTiernan and M A Mathier: These authors contributed equally to this study.

Authors and Affiliations

  1. Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USA

    C F McTiernan, M A Mathier, X Zhu, C H Swan, H Mehdi, G Gibson & B London

  2. Division of Molecular Pharmaceutics, University of North Carolina School of Pharmacy, Chapel Hill, NC, USA

    X Xiao

  3. Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA

    E Klein & A M Trichel

  4. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

    J C Glorioso

  5. Department of Medicine, Jefferson Medical College, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA

    A M Feldman

  6. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    K R McCurry

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  1. C F McTiernan
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  2. M A Mathier
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  3. X Zhu
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  8. G Gibson
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Corresponding author

Correspondence to C F McTiernan.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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McTiernan, C., Mathier, M., Zhu, X. et al. Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts. Gene Ther 14, 1613–1622 (2007). https://doi.org/10.1038/sj.gt.3303020

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