Abstract 15856: BB-R12, a Novel Gene Therapy for Heart Failure
Deoxy-ATP (dATP) exerts positive inotropic effects on cardiomyocytes via a direct interaction with myosin as an alternative energy source to ATP. This allosterically increases the rate of myosin crossbridge binding and cycling with a stronger, faster power stroke. Ribonucleotide Reductase (RNR) generates dATP for DNA synthesis in replicating cells and is down-regulated in cardiomyocytes. BB-R12 is an adeno-associated virus-based gene therapy that over-expresses RNR selectively in cardiomyocytes via the cardiac troponin promoter. Local synthesis of dATP then diffuses via gap junctions throughout the myocardium. BB-R12 improved cardiac function in mouse and rat models of myocardial infarction (MI) and heart failure (HF).
Methods: This is a proof-of-concept study in a large animal MI-HF model. MI with chronic HF was induced in swine by coronary artery occlusion. Two weeks later (Day 0), 1 of 3 doses of BB-R12 or placebo were delivered via antegrade coronary infusion. Left ventricular (LV) performance was measured 1 and 2 months following treatment. Safety and tolerability were assessed.
Results: LV ejection fraction (EF) at baseline was reduced 25-33% at Day 0 by MI. In the high-dose group, at Months 1 and 2, multiple measures of cardiac performance showed substantial reversal of dysfunction compared to further deterioration in the control group (see table). Low and medium doses showed intermediate responses. No differences were observed in histopathologic appearance of hearts or other organs in treated animals compared to controls. No BB-R12 safety or tolerability concerns were noted.
Local cardiac dATP therapy using BB-R12 resulted in reversal of cardiac dysfunction in a large-animal MI-HF model with no safety concerns. As the first gene therapy for HF with a target other than calcium cycling, these results support the therapeutic potential of BB-R12 for patients with chronic heart failure.
Author Disclosures: S.L. Teichman: Employment; Modest; Employed. Ownership Interest; Modest; Equity interest. S. Kadota: Other Research Support; Modest; Research support. M. Regnier: Consultant/Advisory Board; Modest; Advisory Board. C.E. Murry: Consultant/Advisory Board; Modest; Advisory Board. M. Laflamme: Consultant/Advisory Board; Modest; Advisory Board. G.G. Mahairas: Employment; Significant; Employed. Ownership Interest; Modest; Equity interest.
- © 2014 by American Heart Association, Inc.