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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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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DOI: https://doi.org/10.1038/sj.gt.3303020
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