[Development of a Novel Therapeutic for Pediatric Heart Failure Targeting Angiotensin II Receptor].

Abstract

Pediatric drug development is a global challenge. Children undergo organ growth and exhibit different drug reactions than adults, resulting in different pharmacological responses. Therefore, it is necessary to consider children's physiological characteristics when evaluating drug efficacy and safety in pediatric patients. We conducted drug discovery research for the treatment of pediatric heart failure, based on neonatal-specific physiological functions of angiotensin II. Pediatric heart failure is one of the most important causes of death in children, particularly neonates and infants. However, only a few therapeutic agents are available to treat pediatric heart failure. Angiotensin II binds to its receptors (angiotensin II receptor type 1: AT₁R) and regulates cellular functions through G protein and β-arrestin pathways. We previously found that the β-arrestin-biased AT₁R agonist, TRV027, induced a positive inotropic effect in the hearts of neonatal mice. Acute administration of TRV027 did not affect heart rate, oxygen consumption, or production of reactive oxygen species. The inotropic effect of TRV027 was also observed in human iPS cell-derived cardiomyocytes and a neonatal mouse model of dilated cardiomyopathy. Furthermore, chronic administration of TRV027 improved the survival rate of mice with dilated cardiomyopathy during the preweaning period. These results demonstrate that TRV027 has the potential to be a safe and effective drug for treating pediatric heart failure.