Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?
Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?
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DOI：
10.1007/s00395-021-00875-7
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发表时间：
2021-05-20
影响因子：
9.5
通讯作者：
Schneider MD
中科院分区：
文献类型：
--
作者：
Te Lintel Hekkert M;Newton G;Chapman K;Aqil R;Downham R;Yan R;Merkus D;Whitlock G;Lane CAL;Cawkill D;Perrior T;Duncker DJ;Schneider MD
通过干预心肌细胞死亡机制来减少心肌梗死面积(IS)仍然是一个难以实现的目标。DMX-5804是一种选择性的应激激活激酶MAP4K4抑制剂，可以抑制小鼠心肌梗死(MI)、人多能干细胞来源的心肌细胞(hPSC-CMS)和3D人类工程心脏组织的细胞死亡，这些组织对人类生物学的保真度有望加强临床成功的途径。在这里，DMX-10001是一种可溶性的、快速裂解的前药，用于静脉注射。在大型哺乳动物心肌梗死中进行测试。在药效学研究之后，在猪LAD球囊阻断(60min)和再灌注(24h)的基础上进行了随机、盲法疗效研究。36只动物入选；12只因预先定义的标准、输液前死亡或技术问题而被排除在外。DMX-10001于再灌注前20min开始(30min，60 mg/kg/h；23.5h，17 mg/kg/h)。在所有测试时间中，从开始输液后30分钟开始，DMX-5804的浓度超过了拯救 - 的水平的五倍，并在口服DMX-5804本身后降低了小鼠的IS水平。即使DMX-10001减少了27%的IS(以克或LV质量的百分比表示)，IS或无复流校正的缺血风险区域也没有显著的减少。总而言之，一种快速裂解的前药物DMX-5804在大型哺乳动物心肌梗死中未能减少IS，尽管超过了在小鼠和hPSC-CMS中证明成功的浓度。网上版载有补充材料，可在10.1007/s00395-021-00875-7查阅。
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. The online version contains supplementary material available at 10.1007/s00395-021-00875-7.
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DOI：
10.1016/s0140-6736(18)32203-7
发表时间：
2018-11-10
期刊：
Lancet (London, England)
影响因子：
--
作者：
GBD 2017 Causes of Death Collaborators
通讯作者：
GBD 2017 Causes of Death Collaborators
影响因子：
7.5
作者：
Chen, Wei Ren;Chen, Yun Dai;Gu, Xiao Fang
通讯作者：
Gu, Xiao Fang
影响因子：
1.2
作者：
De Wijs-Meijler, Daphne P. M.;Stam, Kelly;Merkus, Daphne
通讯作者：
Merkus, Daphne
DOI：
10.1152/ajpheart.00447.2013
发表时间：
2013-10-01
影响因子：
4.8
作者：
Uitterdijk, Andre;Sneep, Stefan;van Beusekom, Heleen M. M.
通讯作者：
van Beusekom, Heleen M. M.
影响因子：
20.1
作者：
Techiryan G;Weil BR;Palka BA;Canty JM Jr
通讯作者：
Canty JM Jr