Report Summary

Myocarditis Following Adeno-Associated Viral Gene Expression of Human Soluble TNF Receptor (TNFRII.Fc) in Baboon Hearts

Study Summary

Overall Study Design 
Sequestration of TNFa by TNF-receptor IgG-Fc fusion proteins can limit heart failure progression in rodent models In this 
study we directly injected an 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 5x1012 viralgenomesbaboon 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 post-injection 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 
In the United States nearly 4 million people have congestive heart failure CHF and another 400000 are newly diagnosed 
each year Despite advances in pharmacologic support and cardiac assist-device placement CHF presents a grave 
prognosis with a 5-year mortality of 50 Thus the identification of novel therapeutic targets agents and methods of drug 
delivery to improve therapy for CHF remains an important objective 
Heart failure is associated with increased levels of myocardial and circulating proinflammatory cytokines including tumor 
necrosis factor a TNFa1 TNFa adversely modulates cardiomyocyte cellular signaling contractile function and cardiac 
extracellular matrix remodeling In mice cardiac-specific overexpression of TNFa causes dilated cardiomyopathy while 
endogenously produced TNFa contributes to post-infarction remodeling Genetic ablation of TNF receptors or 
administration of anti-TNFa antibodies improves cardiac function and limits remodeling in mouse models of heart failure 
and myocardial infarction A gene therapy approach that expresses soluble TNF-receptor derivatives which sequester TNFa 
can limit cardiac remodeling and heart failure progression in rodent models In humans systemic delivery of human soluble 
TNFa receptor II-Fc fusion protein TNFRII-Fc etanercept via repetitive subcutaneous injection reduces joint inflammation 
and improves symptoms in autoimmune diseases including rheumatoid arthritis and psoriasisHowever subcutaneous 
delivery of etanercept did not show therapeutic benefit in humans with CHF 
Cardiac expression of potentially therapeutic proteins through virally-mediated gene transfer into the myocardium is a 

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