Abstract 911: New Promoters to Improve the Efficiency of Cardiac Gene Therapies Using 2 Deoxy-ATP

• Published in: Circulation research 2019-08, Vol.125 (Suppl_1)
• Main Authors: Robeson, Kalen Z, Moussavi-Harami, Farid, Davis, Jennifer, Regnier, Michal
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.125.suppl_1.911

Abstract only Traditional inotropes work by altering intracellular calcium levels but have many off-target effects. Myosin activators have shown promise for treating the increasing number of heart failure patients today, with one drug in phase three clinical trials. These drugs work by increasing the affinity of myosin for actin. Our lab has demonstrated that the small molecule 2 deoxy-ATP (dATP) can improve both myosin binding to and myosin release from actin. We have also demonstrated the efficacy of a cardiac targeted gene therapy to improve heart function via increasing intracellular dATP levels. This was done by overexpressing ribonucleotide reductase (RNR)—the rate-limiting enzyme in de novo dNTP synthesis. This cardiac therapy, using the cardiac troponin T (cTnT) promoter, was effective in a mouse model but provided variable results in a large animal model due to delivery challenges. Therefore, we are now investigating alternative promoters to deliver dATP to cardiomyocytes and/or other striated muscles. Here we present our investigation of the CK8 promoter for striated muscle specific delivery of RNR. We report that the CK8 promoter was able to produce a greater than fourfold increase in mouse ventricular tissue dATP levels above that seen with the cTnT promoter (2.0 to 8.4 pmol/mg; P