• Text in Japanese

Highlight

• A doctor-initiated clinical trial on the therapeutic effects of transplanting cardiomyocyte sheets made from human iPS cells in patients with severe cardiomyopathy has begun (three patients have already received the transplant)
• This treatment, if successful, would reduce the need for heart donors

Summary

Yoshiki Sawa, Professor, Dept. of Cardiovascular Surgery, Osaka University Graduate School of Medicine, and colleagues, with support from the Japan Agency for Medical Research and Development (AMED), have spent the past many years developing regenerative medicine for the heart based on cardiomyocytes derived from human iPS cells (iPS-cardiomyocytes)¹⁾.  The Sawa group has already tested its human iPS-cardiomyocytes by making them into cardiomyocyte sheets and transplanting the sheets into pigs with poor cardiac function due to ischemic cardiomyopathy²⁾. The lab has also improved its derivation method to make high quality and safe iPS-cardiomyocytes at numbers sufficient to treat human patients. Last year, the group submitted a plan to the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency (PMDA)³⁾ for a doctor-initiated clinical trial⁴⁾ on its iPS cell technology and conducted its first human transplantation in January 2020. As of December 2020, three patients had received the transplantation, completing the first half of the study plan. To date, all patients are progressing well.  

Background of the clinical trial

The Sawa group began researching iPS-cardiomyocytes in 2008 when it began collaborating with Prof. Shinya Yamanaka of Kyoto University. In 2012, the group was the first in the world to use iPS-cardiomyocytes in a pig model of ischemic cardiomyopathy, finding the cells improved cardiac function. Following up on this research, in 2013, it investigated the molecular factors contributing to this improvement and also the electro-functional coupling between the transplanted cells and recipient heart. These studies have helped clarify the mechanism through which iPS-cardiomyocytes improve cardiac function. Now, through modified clinical-grade protocols, including chemical reagents and manufacturing processes, the group has produced iPS-cardiomyocytes at numbers sufficient to form cardiomyocyte sheets that can be transplanted into patients. This doctor-initiated clinical trial aims to measure both the safety and efficacy of the sheets. In total, 10 patients with ischemic cardiomyopathy will be treated. Before proceeding to the next 7 patients, these first 3 patients will be evaluated further. The trial is registered in the Japan Registry of Clinical Trials as jRCT2053190081.

Expected significance

iPS cells were discovered by Prof. Shinya Yamanaka and are expected to have a great impact on new regenerative medicine. The iPS cells used in this clinical trial were made at Kyoto University. Because the iPS cells and iPS-cardiomyocytes can be prepared well before the doctor even has a first consultation with the patient, the wait time for surgery is significantly reduced. Thus, this treatment strategy could become a new standard method for severe heart failure in Japan, where there is a major shortage of heart donors.

Additional Notes

This research is part of the Japan Agency for Medical Research and Development (AMED) Research Center Network for Realization of Regenerative Medicine (Centers for Clinical Application Research on Specific Disease/Organ) and Research Project for Practical Applications of Regenerative Medicine, with support from Professor Shinya Yamanaka and Associate Professor Yoshinori Yoshida of the Center for iPS Cell Research and Application (CiRA), Kyoto University, and Professor Tatsuya Shimizu and Associate Professor Katsuhisa Matsuura of the Institute of Advanced Biomedical Engineering and Science (ABMES), Tokyo Women’s Medical University.

Glossary

1. iPS (induced pluripotent stem) cells
Discovered by Prof. Shinya Yamanaka of Kyoto University, these cells are reprogrammed to an embryonic-like state by the activation of specific transcription factors. In this new state, they can be differentiated to almost any other cell type. Intensive research is ongoing for their application to new regenerative medicine.  

2. Ischemic cardiomyopathy
A disorder in which blood supply to the heart muscles is obstructed, resulting in a weaker heart.

3. PMDA
A national agency that regulates pharmaceuticals and medical devices in Japan along with providing guidance and evaluation to gain approval for clinical trials using these products. The PMDA is also responsible for collecting data on the products post-marketing and delivering responses to side effects.

4. Doctor-initiated clinical trial
Clinical trials are done to test the safety and efficacy of a medical product in order to gain approval from the national government to market the product to the general public. Doctor-initiated clinical trials, as the name suggests, are clinical trials planned by the doctors who conceived and executed the study.