Abstract 10588: Pre-Clinical Study of Induced Pluripotent Stem Cell-Derived Cardiomyocyte Sheet Transplantation for a Cynomolgus Macaque Model of Doxorubicin-Induced Dilated Cardiomyopathy

Abstract

Introduction: Due to the serious shortage of cardiac donors in Japan, there is a strong demand for an effective alternative treatment to heart transplantation (HTx) and left ventricular assist device for end-stage severe heart failure. We have conducted induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) sheet transplantation for ischemic cardiomyopathy as first in human clinical trial (jRCT2053190081), based on several pre-clinical studies suggesting both of angiogenic effects and mechanical contribution of iPSC-CMs. Then, we are next aiming to expand the indication for dilated cardiomyopathy (DCM), which is the most common indication for HTx worldwide. In this study, we established a cynomolgus macaque model of Doxorubicin (Dox)-induced DCM and performed the iPSC-CM sheet transplantation. Methods: Twelve male cynomolgus macaques were treated with Dox to induce DCM every two weeks for three consecutive days in three different doses. The cardiac function was assessed over time by transthoracic echocardiography (TTE) and the effect of doxorubicin on the myocardium was investigated with histological analysis. After the establishment of animal model, we performed the iPSC-CM sheet transplantation and assessed the postoperative cardiac function by TTE and cardiac computed tomography (CT). Results: Each Two macaques treated with high (1.2 kg/mg/day) and medium (1.0 kg/mg/day) dose of Dox died before the establishment of animal model. Of the remaining eight macaques in the low dose (0.8 kg/mg/day) group, six had progressively decreased cardiac function. Histology revealed vacuolization in the left ventricle of the Dox-treated heart. Postoperative evaluation two weeks after iPSC-CM sheet transplantation revealed the improvement in cardiac function on TTE and cardiac CT (left ventricular ejection fraction: from 22 % to 31%, and from 19 % to 31 %, respectively). Conclusions: Three-month administration of low-dose Dox was able to create a cynomolgus macaque model of Dox-induced DCM with relatively high reproducibility. IPSC-CM sheet transplantation may have the possibility for improving cardiac function of DCM.