Clin Res Cardiol 98, Suppl 1, April 2009

V58 - A Novel Treatment Option in Severe Heart Failure by Chronic Cardiac-Targeted RNA Interference for the Silencing of the Phospholamban Gene
L. Suckau1, H. Fechner1, E. Chemaly2, S. Krohn1, L. Hadri2, D. Westermann1, X. Wang1, Y. Kawase2, J. Chen2, L. Liang2, I. Sipo1, R. Vetter3, S. Weger4, J. Kurreck5, C. Tschöpe1, D. Lebeche2, H.-P. Schultheiss1, R. Hajjar2, W. Poller1
1Med. Klinik II, Abt. für Kardiologie und Pulmologie, Charité - Universitätsmedizin Berlin, Campus Benj. Franklin, Berlin; 2Cardiovascular Research Center, Mount Sinai School of Medicine, New York, USA; 3Inst. f. Klinische Pharmakologie u. Toxikologie, Charité - Universitätsmedizin Berlin, Campus Benj. Franklin, CC-04-Therapief., Berlin; 4Charite - Universitätsmedizin Berlin, Institut für Infektionskrankheiten / Campus Benjamin Franklin, Berlin; 5Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin;
RNA interference (RNAi) is a novel therapeutic strategy in cardiovascular medicine. We report on RNAi targeting phospholamban (PLB), a regulator of cardiac Ca2+ homeostasis, for the treatment of heart failure (HF). Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy employs small regulatory RNAs to achieve its effect. Kinetics and toxicity of these RNAs are grossly different from those of proteins. We provide first evidence that they may achieve long-term cardiac benefit without apparent toxicity. We developed an adenoviral RNAi vector (AdV-shRNA) and a series of AAV vectors to optimize their efficacy. A novel AAV9-shPLB vector with optimized RNAi potential was chosen for HF therapy. Transaortic banding (TAB) induced HF in rats. RNAi was initiated by aortic root injection of AdV-shPLB (3x10e10 pfu/a) (Group A) or i.v. injection of AAV9-shPLB (5x10e11 vg/a) (Group B). Group A underwent short-term (1 mo.), Group B long-term therapy (3 mo.), shFGP vectors served as controls. Fig. 1 shows part of hemodynamic improvement (LVEDP, ± dp/dt, FS), hypertrophy reduction (LV/BW, LV/TL, myocyte size, collagen). Survival in group B was increased by AAV9 therapy.


The study demonstrates, for the first time, high efficacy of a local cardiac RNAi therapy. Using optimized RNAi vectors and aortic root vector injection or cardiotropic AAV9 capsids to target RNAi to the heart, there was no evidence of toxicity or disturbed miRNA pathways. AdV-shPLB therapy improved HF 1 mo. after aortic root injection. A novel cardiotropic AAV9-shPLB vector mediated RNAi after simple i.v. injection and improved function, morphology, and survival in severe HF after 3 months.