Cardioprotective Effects of VCP Modulator KUS121 in Murine and Porcine Models of Myocardial Infarction

Abstract

Visual Abstract

The Art of War in Drug Development

“…In addition, the lack of a difference in infarct size reduction between the drug given prior to ischemia and at the time of reperfusion (see Figure 4C and Online Figure 3C in the paper by Ide et al. [4]) suggests rather that ATP preservation is not the major effect or, at least, does not offer additional benefit when the drug is also administered at the time of reperfusion. Meanwhile, infarct size in mice given KUS121 just once at the time of reperfusion was approximately 25% in contrast to approximately 20% in animals given multiple doses after reperfusion.…”

“…In this issue of JACC: Basic to Translational Science , the study by Ide et al. (4) reports a promising new drug for the reduction of myocardial ischemic injury. As suggested by its name, the Kyoto University substance 121 (KUS121) drug is a part of the drug discovery program at the Kyoto University.…”

“…As suggested by its name, the Kyoto University substance 121 (KUS121) drug is a part of the drug discovery program at the Kyoto University. In the study (4), the authors showed that KUS121, a selective inhibitor of the ATPase activity of valosin-containing protein, reduced the size of myocardial infarction (MI) (e.g., 25% of the left ventricle) when it was given prior to ischemia or at the time of reperfusion in mice. After several experiments in mice, the authors extended the study to a pig model of 60-min ischemia-reperfusion and reproduced the beneficial effects observed in mice.…”

“…The mechanism of action seems to be multimodal. Using in vitro systems and mouse models, the authors showed inhibition of endoplasmic reticulum (ER) stress, preservation of mitochondrial function, and preservation of myocardial ATP as potential contributors (4). The main strength of the study by Ide et al.…”

“…The main strength of the study by Ide et al. (4) is its use of several experimental models from cells to pigs, rendering the study highly translational. Streamlined translational experiments certainly expedite the drug development process, and the authors already foresee a clinical trial.…”