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


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.
Pinkert
Sandra
S
Department of Cardiology & Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
Westermann
Dirk
D
Wang
Xiaomin
X
Klingel
Karin
K
Dörner
Andrea
A
Savvatis
Konstantinos
K
Grössl
Tobias
T
Krohn
Stefanie
S
Tschöpe
Carsten
C
Zeichhardt
Heinz
H
Kotsch
Katja
K
Weitmann
Kerstin
K
Hoffmann
Wolfgang
W
Schultheiss
Heinz-Peter
HP
Spiller
O Brad
OB
Poller
Wolfgang
W
Fechner
Henry
H
D000208:Acute Disease; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000517:prevention & control / Q000821:virology; D003384:Coxsackievirus Infections / Q000235:genetics / Q000517:prevention & control*; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000235:genetics / Q000517:prevention & control* / Q000821:virology; D011991:Receptors, Virus / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*
D011991:Receptors, Virus; C105941:coxsackievirus B receptor