title: Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice.
abstract: BACKGROUND
  Coxsackievirus B3 (CVB3) is a major heart pathogen against which no therapy exists to date. The potential of a combination treatment consisting of a proteinaceous virus receptor trap and an RNA interference-based component to prevent CVB3-induced myocarditis was investigated.
  
  
  RESULTS
  A soluble variant of the extracellular domain of the coxsackievirus-adenovirus receptor (sCAR-Fc) was expressed from an adenoviral vector and 2 short hairpin RNAs (shRdRp2.4) directed against CVB3 were delivered by an adeno-associated virus (AAV) vector. Cell culture experiments revealed additive antiviral activity of the combined application. In a CVB3-induced mouse myocarditis model, both components applied individually significantly reduced inflammation and viral load in the heart. The combination exerted an additive antiviral effect and reduced heart pathology. Hemodynamic measurement revealed that infection with CVB3 resulted in impaired heart function, as illustrated by a drastically reduced cardiac output and impaired contractility and relaxation. Treatment with either sCAR-Fc or shRdRp2.4 significantly improved these parameters. Importantly, the combination of both components led to a further significant improvement of heart function.
  
  
  CONCLUSIONS
  Combination of sCAR-Fc and shRdRp2.4 exerted additive effects and was significantly more effective than either of the single treatments in inhibiting CVB3-induced myocarditis and preventing cardiac dysfunction.
authors.affiliation: Department of Applied Biochemistry, Technische Universität Berlin, Institute of Biotechnology.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Stein
authors.affiliation: Department of Applied Biochemistry, Technische Universität Berlin, Institute of Biotechnology.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinkert
authors.affiliation: Department of General and Interventional Cardiology, University Heart Center Hamburg Eppendorf.
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.affiliation: Department of Applied Biochemistry, Technische Universität Berlin, Institute of Biotechnology.
authors.forename: Anja
authors.initials: A
authors.lastname: Geisler
authors.affiliation: Campus Benjamin Franklin, Institute for Virology, Charité-Universitätsmedizin Berlin.
authors.forename: Heinz
authors.initials: H
authors.lastname: Zeichhardt
authors.affiliation: Institute of Veterinary Pathology, Freie Universität Berlin.
authors.forename: Robert
authors.initials: R
authors.lastname: Klopfleisch
authors.affiliation: Campus Benjamin Franklin, Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.affiliation: Campus Benjamin Franklin, Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: IKDT Institut Kardiale Diagnostik und Therapie GmbH, Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lassner
authors.affiliation: Department of Applied Biochemistry, Technische Universität Berlin, Institute of Biotechnology.
authors.forename: Henry
authors.initials: H
authors.lastname: Fechner
authors.affiliation: Department of Applied Biochemistry, Technische Universität Berlin, Institute of Biotechnology.
authors.forename: Jens
authors.initials: J
authors.lastname: Kurreck
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000821:virology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D029822:Enterovirus B, Human / Q000187:drug effects*; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000821:virology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering; D011991:Receptors, Virus
keywords: RNA interference; coxsackievirus; gene therapy; myocarditis; viruses