期刊
BASIC RESEARCH IN CARDIOLOGY
卷 116, 期 1, 页码 -出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-021-00875-7
关键词
Cardioprotection; Drug development; Human pluripotent stem cell-derived cardiomyocytes; Infarct size
资金
- Wellcome Trust [WT10638/Z/14/Z, WT205256/Z/16/Z]
- Apollo Therapeutics [AP22]
- British Heart Foundation [CH/08/002/29257]
A study was conducted to test the efficacy of DMX-10001, a pro-drug of DMX-5804, in reducing infarct size in large-mammal myocardial infarction. Despite exceeding the concentrations proven successful in mice and hPSC-CMs, DMX-10001 failed to reduce infarct size in large-mammals.
Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded>fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据