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

C F McTiernan; M A Mathier; X Zhu; X Xiao; E Klein; C H Swan; H Mehdi; G Gibson; A M Trichel; J C Glorioso; A M Feldman; K R McCurry; B London

doi:10.1038/sj.gt.3303020

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

Journal article

Peer reviewed

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

C F McTiernan, M A Mathier, X Zhu, X Xiao, E Klein, C H Swan, H Mehdi, G Gibson, A M Trichel, J C Glorioso, …

Gene therapy, Vol.14(23), pp.1613-1622

12/2007

DOI: 10.1038/sj.gt.3303020

PMID: 17851548

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Abstract

Sequestration of tumor necrosis factor-alpha (TNFalpha) 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 ( approximately 5 x 10(12) 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 approximately 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.

Dependovirus - genetics

Myocardium - immunology

Genetic Vectors - administration & dosage

Male

Receptors, Tumor Necrosis Factor, Type II - genetics

Genetic Vectors - genetics

Papio

Myocarditis - virology

Injections

Animals

Models, Animal

CD8-Positive T-Lymphocytes - immunology

Immunoglobulin Fc Fragments - genetics

Myocarditis - immunology

Microscopy, Fluorescence

Recombinant Fusion Proteins - administration & dosage

Genetic Therapy - adverse effects

Genetic Therapy - methods

Details

Title: Subtitle: Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts
Creators: C F McTiernan - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA. mctiernanc@upmc.edu
M A Mathier
X Zhu
X Xiao
E Klein
C H Swan
H Mehdi
G Gibson
A M Trichel
J C Glorioso
A M Feldman
K R McCurry
B London
Resource Type: Journal article
Publication Details: Gene therapy, Vol.14(23), pp.1613-1622
DOI: 10.1038/sj.gt.3303020
PMID: 17851548
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Publisher: England
Grant note: U01HL66949 / NHLBI NIH HHS
Language: English
Date published: 12/2007
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984025685302771

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