Evaluation of the Efficacy and Safety of a Clinical Grade Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Patch: A Pre-Clinical Study

Abstract

Aims: Cardiomyocyte-derived induced pluripotent stem cells (iPSCs) may represent a promising therapeutic strategy for severely damaged myocardium. This study aimed to assess the efficacy and safety of clinical grade human iPSC-derived cardiomyocyte (hiPSC-CM) patches and conduct a pre-clinical proof-of-concept analysis. Methods and results: A clinical grade hiPSC line was established from peripheral blood mononuclear cells collected from a healthy volunteer homozygous for human leukocyte antigens and differentiated into cardiomyocytes using cytokines and chemical compounds. hiPSC-CMs were cultured on temperature-responsive culture dishes to fabricate the hiPSC-CM patch. The hiPSC-CMs expressed cardiomyocyte-specific genes and proteins while electrophysiological analyses revealed that hiPSC-CMs were similar to the human myocardium. In vitro safety studies using cell growth, soft agar colony formation, and undifferentiated cell assays indicated that tumourigenic cells were not present. Moreover, no genomic mutations were discovered using whole genome and exome sequencing analysis. Tumour formation was not detected in an in vivo tumourigenicity assay using NOG mice. General toxicity tests also showed no adverse events due to hiPSC-CM patch transplantation. An efficacy study using a porcine model of myocardial infarction demonstrated significantly improved cardiac function with angiogenesis and a reduction in interstitial fibrosis, which was enhanced by cytokine secretion from hiPSC-CM patches after transplantation. No lethal arrhythmias were observed. Conclusion: hiPSC-CM patches show promise for future translational research and clinical trials for ischaemic heart failure.

Transplantation of IPSC-Derived Cardiomyocyte Patches for Ischemic Cardiomyopathy

“…Transplanted cardiomyocyte patches have been reported to undergo contraction/relaxation 23 or repeated electrical potential activation 24 in the recipient heart in a synchronous fashion. The cardiogenic properties (both histological and functional) of cardiomyocyte patches were also demonstrated in our preclinical study 11 (Figure 1).…”

“…The methods for establishing clinical-grade hiPSCs and generation of master cell is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint bank (MCB) of the hiPSC-cell line (QHJI14s04) have been described elsewhere 11 .…”

“…The detailed characterization of the hiPSCs and the MCB are presented elsewhere 11 and Supplemental Data (Online Table ), respectively. The hiPSC-CM patch used in this clinical trial was prepared by a method that cleared the tumorigenicity denial test shown elsewhere 11 . The hiPSC-CM cells used passed all quality inspections, as shown in Table 1.…”

“…The methods for establishing clinical-grade hiPSCs and generation of master cell bank (MCB) of the hiPSC-cell line (QHJI14s04) have been described elsewhere 11 .…”

“…QHJI14s04 was generated using episomal plasmids (pCE-hSK, pCE-hUL, pCE-hOCT3/4, pCE-mp53DD, pCXB-EBNA1) and maintained using a feeder-free and xeno-free culture system 13 in the cell processing center (Facility for iPS Cell Therapy, CiRA). The evaluation method for ensuring quality and the results are reported separately 11 . For the production of hiPSC-CMs, the MCB of QHJI14s04 was established under good manufacturing practice conditions.…”