Case report: Transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy

Abstract

Despite major therapeutic advances, heart failure, as a non-communicable disease, remains a life-threatening disorder, with 26 million patients worldwide, causing more deaths than cancer. Therefore, novel strategies for the treatment of heart failure continue to be an important clinical need. Based on preclinical studies, allogenic human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches have been proposed as a potential therapeutic candidate for heart failure. We report the implantation of allogeneic hiPSC-CM patches in a patient with ischemic cardiomyopathy (ClinicalTrials.gov, #jRCT2053190081). The patches were produced under clinical-grade conditions and displayed cardiogenic phenotypes and safety in vivo (severe immunodeficient mice) without any genetic mutations in cancer-related genes. The patches were then implanted via thoracotomy into the left ventricle epicardium of the patient under immunosuppressive agents. Positron emission tomography and computed tomography confirmed the potential efficacy and did not detect tumorigenesis in either the heart or other organs. The clinical symptoms improved 6 months after surgery, without any major adverse events, suggesting that the patches were well-tolerated. Furthermore, changes in the wall motion in the transplanted site were recovered, suggesting a favorable prognosis and the potential tolerance to exercise. This study is the first report of a successful transplant of hiPSC-CMs for severe ischemic cardiomyopathy.

Keywords: clinical trial; human induced pluripotent stem cell-derived cardiomyocyte; ischemic cardiomyopathy; regenerative therapy; transplantation.

Figure 1

Timeline of symptoms and treatment and the clinical trial flowchart of the human induced pluripotent stem (iPS) cell-derived cardiomyocyte (hiPSC-CM) patches. (A) The date in parentheses indicates the number of days since the first attack. The patient underwent anti-heart failure medications (maximum dosages), such as beta-blockers, ACE inhibitors, and diuretics, before transplantation. In the first 3 months after transplantation, the patient received immunosuppressant drugs, including steroids, tacrolimus hydrate, and mycophenolic acid (mofetil); thereafter, these drugs were discontinued. Notably, no medications were introduced/stopped post transplantation. (B) The clinical trial flowchart of hiPSC-CM patches. Clinical-grade iPS cells were established and procured from CiRA (Kyoto University). The hiPSC-CM patches were manufactured in the cell processing center in Osaka University Hospital using the MCB cells generated in the Center for Gene and Cell Processing of Takara Bio Inc. (Kusatsu, Japan). The following quality inspections were performed during the manufacturing process: QC1: Quality check of the MCB (7). The detailed procedure of the generation of MCB is described elsewhere (7). QC2: viability, purity of cardiomyocytes, sterility, mycoplasma testing, and endotoxin testing (Supplementary Table 1). CAG, coronary angiography; RCA, right coronary artery; LCX, left circumflex coronary artery branch; LAD, left anterior descending coronary artery; PCI, percutaneous coronary intervention; LMT, left main coronary trunk; AV, atrioventricular node branch; ACS, acute coronary syndrome; IABP, intra-aortic balloon pumping; PCPS, percutaneous cardiopulmonary support; and ACE, angiotensin-converting enzyme; iPS, induced pluripotent stem; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; MCB, master cell bank.

Figure 2

Transplantation of hiPSC-CM and cardiac moving pattern before and after surgery. (A) First transplantation of hiPSC-CM patches onto the heart surface of a patient with severe cardiomyopathy. Left: hiPSC-CM patch was transplanted into the epicardium of the anterior and lateral walls of the LV through the fourth intercostal space under IABP support. Right: Three patches were transplanted into the epicardium of the LV anterior and lateral walls. (B) The moving pattern observed via four-dimensional CT. Colors were set so that red indicated a good dynamic area; the darker the color, the lower the movement. The images show the moving pattern in chronological order of the heart at pre-implantation (pre), 6 months, and 1 year after implantation. The dotted line in the bottom figure shows the area where the patches were attached. hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; LV, left ventricle; IABP, intra-aortic balloon pumping; CT, computed tomography.

Figure 3

Changes in end-systolic wall stress. (A) Bull's-eye grid showing the changes in end-systolic wall stress before and 6 months after surgery, calculated by computed tomography. Red and orange highlight the areas of reduction in wall stress by over 20 and 10–20%, respectively. Light blue highlights the remaining areas. (B) Change in the global (left) and regional (transplanted area, right) end-systolic wall stress 6 months after transplantation.

Figure 4

¹³N-ammonia PET images of myocardial blood flow at rest and during stress after hiPSC-CM sheet implantation. (A) Color-coded polar maps with superimposed 17-segment bull's-eye grids with blood flow quantitated under stress and at rest, as well as flow reserve values, are shown in each segment (upper figures). Myocardial blood flow images (short axis) are shown in the lower figures. Red arrows indicate preserved myocardial flow reserves in the anteroseptal to lateral segments. The areas surrounded by the dotted line in the flow reserve figure show a: anteroseptal, b: anterior, and c: anterolateral regions, and the average values of the two area parts were calculated. (B) Change in myocardial blood flow. Myocardial blood flow in the segmental regions LAD, Cx, and RCA at rest and under stress. (C) Change in myocardial flow reserve. Myocardial flow reserve in the whole and each segmental region at 6 months and 1 year after hiPSC-CM patch transplantation. ¹³N-ammonia PET, ¹³N-ammonia positron emission tomography; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; LAD, left anterior descending coronary artery; Cx, circumflex coronary artery; RCA, Right coronary artery.