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. METHODS AND 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.
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. METHODS AND 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-failurerats 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: Kobra Haghighi; Fotis Kolokathis; Anthony O Gramolini; Jason R Waggoner; Luke Pater; Roy A Lynch; Guo-Chang Fan; Dimitris Tsiapras; Rohan R Parekh; Gerald W Dorn; David H MacLennan; Dimitrios Th Kremastinos; Evangelia G Kranias Journal: Proc Natl Acad Sci U S A Date: 2006-01-23 Impact factor: 11.205
Authors: Christina A Pacak; Cathryn S Mah; Bijoy D Thattaliyath; Thomas J Conlon; Melissa A Lewis; Denise E Cloutier; Irene Zolotukhin; Alice F Tarantal; Barry J Byrne Journal: Circ Res Date: 2006-07-27 Impact factor: 17.367
Authors: Thomas Dieterle; Markus Meyer; Yusu Gu; Darrell D Belke; Eric Swanson; Mitsuo Iwatate; John Hollander; Kirk L Peterson; John Ross; Wolfgang H Dillmann Journal: Cardiovasc Res Date: 2005-09-01 Impact factor: 10.787
Authors: Eva van Rooij; Lillian B Sutherland; Ning Liu; Andrew H Williams; John McAnally; Robert D Gerard; James A Richardson; Eric N Olson Journal: Proc Natl Acad Sci U S A Date: 2006-11-15 Impact factor: 11.205
Authors: Lourdes M Andino; Morihiko Takeda; Hideko Kasahara; Andrew Jakymiw; Barry J Byrne; Alfred S Lewin Journal: J Gene Med Date: 2008-02 Impact factor: 4.565
Authors: Wen Zhao; Qunying Yuan; Jiang Qian; Jason R Waggoner; Anand Pathak; Guoxiang Chu; Bryan Mitton; Xiaoyin Sun; Jay Jin; Julian C Braz; Harvey S Hahn; Yehia Marreez; Faisal Syed; Piero Pollesello; Arto Annila; Hong-Sheng Wang; Jo El J Schultz; Jeffery D Molkentin; Stephen B Liggett; Gerald W Dorn; Evangelia G Kranias Journal: Circulation Date: 2006-02-13 Impact factor: 29.690
Authors: Wolfgang Poller; Stefanie Dimmeler; Stephane Heymans; Tanja Zeller; Jan Haas; Mahir Karakas; David-Manuel Leistner; Philipp Jakob; Shinichi Nakagawa; Stefan Blankenberg; Stefan Engelhardt; Thomas Thum; Christian Weber; Benjamin Meder; Roger Hajjar; Ulf Landmesser Journal: Eur Heart J Date: 2018-08-01 Impact factor: 29.983