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

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/dt(max) 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/dt(min) -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/dt(max) 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.

CONCLUSIONS:

AdG12-mediated sCAR-Fc delivery prevents cardiac dysfunction in CVB3 myocarditis under prophylactic and therapeutic conditions.

• Authors: Sandra Pinkert, Dirk Westermann, Xiaomin Wang, Karin Klingel, Andrea Dörner, Konstantinos Savvatis, Tobias Grössl, Stefanie Krohn, Carsten Tschöpe, Heinz Zeichhardt, Katja Kotsch, Kerstin Weitmann, Wolfgang Hoffmann, Heinz-Peter Schultheiss, O Brad Spiller, Wolfgang Poller, Henry Fechner
• Journal: Circulation (Circulation) Vol. 120 Issue 23 Pg. 2358-66 (Dec 08 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19933937 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Virus
• coxsackievirus B receptor

Topics

• Acute Disease
• Animals
• Cardiomyopathies (genetics, prevention & control, virology)
• Coxsackievirus Infections (genetics, prevention & control)
• Gene Expression Regulation, Viral
• Genetic Therapy (methods)
• HeLa Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Myocarditis (genetics, prevention & control, virology)
• Receptors, Virus (administration & dosage, biosynthesis, genetics)