Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy.
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.
Suckau
Lennart
L
Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Germany.
Fechner
Henry
H
Chemaly
Elie
E
Krohn
Stefanie
S
Hadri
Lahouaria
L
Kockskämper
Jens
J
Westermann
Dirk
D
Bisping
Egbert
E
Ly
Hung
H
Wang
Xiaomin
X
Kawase
Yoshiaki
Y
Chen
Jiqiu
J
Liang
Lifan
L
Sipo
Isaac
I
Vetter
Roland
R
Weger
Stefan
S
Kurreck
Jens
J
Erdmann
Volker
V
Tschope
Carsten
C
Pieske
Burkert
B
Lebeche
Djamel
D
Schultheiss
Heinz-Peter
HP
Hajjar
Roger J
RJ
Poller
Wolfgang C
WC
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
D002118:Calcium; D002135:Calcium-Binding Proteins; D035683:MicroRNAs; D000099211:Phospholamban