Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts.
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.
McTiernan
C F
CF
Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA. mctiernanc@upmc.edu
Mathier
M A
MA
Zhu
X
X
Xiao
X
X
Klein
E
E
Swan
C H
CH
Mehdi
H
H
Gibson
G
G
Trichel
A M
AM
Glorioso
J C
JC
Feldman
A M
AM
McCurry
K R
KR
London
B
B
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007267:Injections; D008297:Male; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D009205:Myocarditis / Q000276:immunology / Q000821:virology*; D009206:Myocardium / Q000276:immunology; D010215:Papio; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage
D007141:Immunoglobulin Fc Fragments; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins