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Prevention of cardiac dysfunction in acute coxsackievirus B3 cardiomyopathy by inducible expression of a soluble coxsackievirus-adenovirus receptor

Pinkert, Sandra, Westermann, Dirk, Wang, Xiaomin, Klingel, Karin, Dorner, Andrea, Savvatis, Konstantinos, Grossl, Tobias, Krohn, Stefanie, Tschope, Carsten, Zeichhardt, Heinz, Kotsch, Katja, Weitmann, Kerstin, Hoffmann, Wolfgang, Schultheiss, Heinz-Peter, Spiller, Owen Bradley, Poller, Wolfgang and Fechner, Henry 2009. Prevention of cardiac dysfunction in acute coxsackievirus B3 cardiomyopathy by inducible expression of a soluble coxsackievirus-adenovirus receptor. Circulation 120 (23) , pp. 2358-2366. 10.1161/CIRCULATIONAHA.108.845339

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Abstract

Background— Group B coxsackieviruses (CVBs) are the prototypical agents of acute myocarditis and chronic dilated cardiomyopathy, but an effective targeted therapy is still not available. Here, we analyze the therapeutic potential of a soluble (s) virus receptor molecule against CVB3 myocarditis using a gene therapy approach. Methods and Results— We generated an inducible adenoviral vector (AdG12) for strict drug-dependent delivery of sCAR-Fc, a fusion protein composed of the coxsackievirus-adenovirus receptor (CAR) extracellular domains and the carboxyl terminus of human IgG1-Fc. Decoy receptor expression was strictly doxycycline dependent, with no expression in the absence of an inducer. CVB3 infection of HeLa cells was efficiently blocked by supernatant from AdG12-transduced cells, but only in the presence of doxycycline. After liver-specific transfer, AdG12 (plus doxycycline) significantly improved cardiac contractility and diastolic relaxation compared with a control vector in CVB3-infected mice if sCAR-Fc was induced before infection (left ventricular pressure 59±3.8 versus 45.4±2.7 mm Hg, median 59 versus 45.8 mm Hg, P<0.01; dP/dtmax 3645.1±443.6 versus 2057.9±490.2 mm Hg/s, median 3526.6 versus 2072 mm Hg/s, P<0.01; and dP/dtmin −2125.5±330.5 versus −1310.2±330.3 mm Hg/s, median −2083.7 versus −1295.9 mm Hg/s, P<0.01) and improved contractility if induced concomitantly with infection (left ventricular pressure 76.4±19.2 versus 56.8±10.3 mm Hg, median 74.8 versus 54.4 mm Hg, P<0.05; dP/dtmax 5214.2±1786.2 versus 3011.6±918.3 mm Hg/s, median 5182.1 versus 3106.6 mm Hg/s, P<0.05), respectively. Importantly, hemodynamics of animals treated with AdG12 (plus doxycycline) were similar to uninfected controls. Preinfection induction of sCAR-Fc completely blocked and concomitant induction strongly reduced cardiac CVB3 infection, myocardial injury, and inflammation. Conclusion— AdG12-mediated sCAR-Fc delivery prevents cardiac dysfunction in CVB3 myocarditis under prophylactic and therapeutic conditions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: receptors; viruses; myocarditis; gene therapy; coxsackieviruses
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0009-7322/ (accessed 19/02/2014).
Publisher: American Heart Association
ISSN: 0009-7322
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 03:50
URI: http://orca-mwe.cf.ac.uk/id/eprint/27713

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