Thomson Kassandra S, Odom Guy L, Murry Charles E, Mahairas Gregory G, Moussavi-Harami Farid, Teichman Sam L, Chen Xiaolan, Hauschka Stephen D, Chamberlain Jeffrey S, Regnier Michael
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Department of Neurology, University of Washington, Seattle, Washington, USA.
JACC Basic Transl Sci. 2016 Dec;1(7):666-679. doi: 10.1016/j.jacbts.2016.07.006.
Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms, and improve functional capacity and quality of life. We discovered small amounts of 2-deoxy-ATP (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin crossbridge cycling with greater force generation during each contraction. We describe the rationale and results of a translational medicine effort to increase dATP levels using a gene therapy strategy that upregulates ribonucleotide reductase, the rate-limiting enzyme for dATP synthesis, selectively in cardiomyocytes. In small and large animal models of heart failure, a single dose of this gene therapy has led to sustained inotropic effects with no toxicity or safety concerns identified to-date. Further animal studies are being conducted with the goal of testing this agent in patients with heart failure.
尽管近年来取得了进展，但慢性心力衰竭仍然是一个重大且不断增长的未满足医疗需求，已达到流行程度，带来了大量的发病率、死亡率和成本。一种能产生持续正性肌力作用的安全便捷治疗药物可以改善症状，提高功能能力和生活质量。我们发现少量的2-脱氧三磷酸腺苷（dATP）可激活心肌肌球蛋白，从而增强正常和衰竭心肌的收缩力。心肌肌球蛋白的激活触发了更快的肌球蛋白横桥循环，在每次收缩时产生更大的力量。我们描述了一项转化医学研究的原理和结果，该研究采用基因治疗策略来提高dATP水平，该策略可在心肌细胞中选择性地上调核糖核苷酸还原酶，这是dATP合成的限速酶。在心力衰竭的小型和大型动物模型中，单剂量的这种基因治疗已产生持续的正性肌力作用，迄今为止未发现毒性或安全问题。目前正在进行进一步的动物研究，目标是在心力衰竭患者中测试这种药物。
