title: Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy.
abstract: BACKGROUND
  RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. Here, we report on targeted RNAi for the treatment of heart failure, an important disorder in humans that results from multiple causes. Successful treatment of heart failure is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban, a key regulator of cardiac Ca(2+) homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy uses regulatory RNAs to achieve its effect.
  
  
  RESULTS
  We describe structural requirements to obtain high RNAi activity from adenoviral and adeno-associated virus (AAV9) vectors and show that an adenoviral short hairpin RNA vector (AdV-shRNA) silenced phospholamban in cardiomyocytes (primary neonatal rat cardiomyocytes) and improved hemodynamics in heart-failure rats 1 month after aortic root injection. For simplified long-term therapy, we developed a dimeric cardiotropic adeno-associated virus vector (rAAV9-shPLB) to deliver RNAi activity to the heart via intravenous injection. Cardiac phospholamban protein was reduced to 25%, and suppression of sacroplasmic reticulum Ca(2+) ATPase in the HF groups was rescued. In contrast to traditional vectors, rAAV9 showed high affinity for myocardium but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (left ventricular end-diastolic pressure, dp/dt(min), and tau) and systolic (fractional shortening) functional parameters to normal ranges. The massive cardiac dilation was normalized, and cardiac hypertrophy, cardiomyocyte diameter, and cardiac fibrosis were reduced significantly. Importantly, no evidence was found of microRNA deregulation or hepatotoxicity during these RNAi therapies.
  
  
  CONCLUSIONS
  Our data show for the first time the high efficacy of an RNAi therapeutic strategy in a cardiac disease.
authors.affiliation: Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Germany.
authors.forename: Lennart
authors.initials: L
authors.lastname: Suckau
authors.forename: Henry
authors.initials: H
authors.lastname: Fechner
authors.forename: Elie
authors.initials: E
authors.lastname: Chemaly
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krohn
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Egbert
authors.initials: E
authors.lastname: Bisping
authors.forename: Hung
authors.initials: H
authors.lastname: Ly
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Chen
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.forename: Isaac
authors.initials: I
authors.lastname: Sipo
authors.forename: Roland
authors.initials: R
authors.lastname: Vetter
authors.forename: Stefan
authors.initials: S
authors.lastname: Weger
authors.forename: Jens
authors.initials: J
authors.lastname: Kurreck
authors.forename: Volker
authors.initials: V
authors.lastname: Erdmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschope
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Wolfgang C
authors.initials: WC
authors.lastname: Poller
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D035683:MicroRNAs / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D035683:MicroRNAs; D000099211:Phospholamban