Clin Res Cardiol 98, Suppl 1, April 2009

V55 - Regulatable Expression of a Recombinant Soluble Coxsackievirus-Adenovirus-Receptor (CAR) Fusion Protein Prevents Coxsackievirus B3-Induced Cardiomyopathy in vivo
 
S. Pinkert1, D. Westermann1, X. Wang1, K. Klingel2, A. Dörner1, K. Savvatis1, B. Spiller3, C. Tschöpe1, H.-P. Schultheiss1, H. Fechner1, W. Poller1
 
1Med. Klinik II, Abt. für Kardiologie und Pulmologie, Charité - Universitätsmedizin Berlin, Campus Benj. Franklin, Berlin; 2Institut für Pathologie, Universitätsklinikum Tübingen, Tübingen; 3Department of Child Health, Cardiff University School of Medicine, Cardiff, Großbritannien;
 
Coxsackieviruses of subgroup B (CVB) are prototype agents of acute myocarditis and chronic dilatative cardiomyopathy (DCM) but an effective targeted therapy is still not available. Here we analyze the therapeutic potential of a soluble (s) virus receptor against CVB3 myocarditis by use of a gene therapy approach. We generated an adenoviral vector (AdG12) for drug inducible delivery of a sCAR-Fc a fusion protein consisting of the extracellular domain of the Coxsackievirus-Adenovirus-Receptor (CAR) and the carboxyl terminus of human IgG1 Fc. Decoy receptor expression was strictly doxycycline (Dox)-dependent, with no expression in the absence of inducer. CVB3 infection of HeLa cells was efficiently blocked by supernatant from AdG12 transduced cells, but only in the presence of Dox. Following liver specific transfer, AdG12 (+Dox) significantly improved cardiac contractility and diastolic relaxation compared to the control AdG12 (-Dox) in CVB3 infected mice (dP/dtmax 3645.1±443 vs. 2057.9±490 mmHg/s, p<0.001; LVP 59±4 vs. 45.4±3 mmHg/s, p<0.001; dP/dtmin -2125.5±282 vs. -1143.6±246 mmHg/s, p<0.001). Importantly, hemodynamics of animals treated with activated AdG12 were similar to uninfected controls. Activated AdG12 prevented myocardial infection with CVB3 and completely blocked myocardial injury and inflammation in vivo (Fig. 1).
 

 


Thus, AdG12-mediated sCAR-Fc delivery is the first treatment which completely prevents CVB3 myocarditis and heart dysfunction. The strength of the effect and the added safety of complete Dox-dependence of expression make this a promising approach for the treatment of this life-threatening cardiac disease.
 


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