Human whole genome sequencing and the progress in the elucidation of a biological reaction network have resulted in a new scientific term: bioinformatics. Currently, a number of biological events can be explained at the molecular level. The acceleration of research and development in life sciences has led to a global trend: the 21st century is the biotechnology era [1]. In Japan, the Biotechnology Strategy Council, established by the Cabinet Office of the Japanese government issued “Strategies for the Development of Biotechnology” in December 2002 as a vision of the 21st century ^[2][3][4][2,3,4]. This report proposed a new direction in science and technology, i.e., a shift from electronics to biotechnology. In response to this report, the Project for Realization of Regenerative Medicine was launched in 2003 [5].

Regenerative medicine originates from stem cell biology in embryology. The therapeutic concept is to restore the function of damaged organs and tissues by stem cells. The implantation or mobilization of stem cells shows unique potency not yet seen in existing pharmaceuticals, and the cell itself is being recognized as a new medicinal category. In particular, such therapy is expected to replace organ transplantation, which has a serious long-lasting donor shortage. In research and development, somatic stem cells and embryonic stem (ES) cells preceded and induced pluripotent stem cells (iPS) cells established by Shinya Yamanaka, a Nobel Prize awardee in 2012 ^[6][7][6,7]. iPS cells enable the use of autologous pluripotent stem cells, which are produced from somatic cells, and resolve not only the issue of the immunological rejection but also the ethical concerns of ES cells. The establishment of iPS cells was an epochal achievement of the biotechnology era in Japan.

2. Preclinical Research Projects Aiming at the Transition to Clinical Trials

The Highway Program for Realization of Regenerative Medicine and the Program of the Research Center Network for Realization of Regenerative Medicine recruited 18 scientific projects, 1 foundational platform, and 2 support programs. The objective was to start clinical trials in 3 to 7 years. The scientific projects were categorized by the use of human somatic cells and the use of human iPS and ES cells. The former includes treatments for articular cartilage, corneal endothelium, liver cirrhosis, and intestinal epithelium, totaling five projects. The latter include treatments involving the eye (three projects), central nervous system (two projects), heart (two projects), liver (two projects), articular cartilage (one project), pancreatic islets (one project), and immune system (one project), totaling 13 projects, one of which involves the application of human ES cells and the rest the application of human iPS cells. Supporting programs cover regulation and ethical, legal, and social issues (ELSI), and the two teams organized regular meetings to instruct on key issues for the successful transition to clinical trials in a cross-sectoral manner. Each project has its own originality based on the preceding research with somatic stem cells as well as human ES and iPS cells. Sekiya et al. first determined the superiority of mesenchymal stem cells isolated from synovium in chondrogenesis activity compared to stem cells from bone marrow, periosteum, skeletal muscle, and adipose tissue [8] and confirmed the repairing ability in a rabbit osteochondral defect model in vivo [9]. To obtain cells for transplantation of corneal endothelium, the disfunction of which induces a serious homeostatic imbalance of the anterior hydatoid, a ROCK inhibitor treatment was effective in triggering the cells’ proliferation, which was otherwise static ^[10][11]. The procedure enabled the novel treatment of cell engraftment for corneal endothelium disorder instead of corneal tissue transplantation ^[11][10]. The therapeutic potential of mesenchymal stem cells in the amelioration of cirrhotic liver has been investigated using autologous bone marrow cells [12]. However, it is often hard to harvest enough cells from patients with liver cirrhosis under general anesthesia. Thus, a method to increase the number of cells prior to transplantation was established [13]. In the mesenchymal stem cell therapy of knee joint cartilage, the preloading of magnetic beads with a medical grade helped to position the cells in the most effective place for the treatment [14]. The colonic stem cell-derived organoids showed the integration and repairment of an artificial ulcer in mouse colon, promising clinical application for inflammatory bowel diseases [15]. Most of the projects involving human iPS and ES cells are aimed at the transplantation of manufactured tissue to replace diseased tissue. All of the studies proposed the resolution of unmet medical needs by producing cells and tissues through quality controlled processing. For instance, the target disease of the retinal tissue regeneration was age-related macular degeneration ^[16][17][16,17]. There are a number of patients but still few effective treatments, except for the periodic topical injection of anti-vascular endothelial growth factor (VEGF) antibody to suppress retinal pathogenic thickening. Translocation of the perimacular area of a patient’s own retina to the diseased macular area was tried using intraocular microsurgery ^[18][36], but it is not conducted at present because of the invasiveness and lack of an obvious effect. Transplantation of stem cell-derived retinal tissue is hoped to be a permanent treatment, especially in order to escape the need for regular injections. In addition, there are also ethical rationales for conducting such clinical trials: (1) the disease is not life-threatening but highly impairs the quality of life; (2) the intraocular region is an immune privilege site; (3) carcinogenesis in the retina is very rare in adults. The project involving cell transplantation for Parkinson’s disease proposes to use human iPS cell-derived dopamine-producing cells ^[19][21]. A similar treatment was attempted with allogeneic fetal olfactory mucosal cells isolated from aborted fetus ^[20][21][37,38]. The procedure involved serious ethical issues and the effect was disputable. Olfactory cells contain not only dopamine- but also serotonin-secreting cells, which are not effective but rather aggravative toward neurological symptoms. The project aims to procure and transplant purified dopamine-producing cells under well-controlled cell processing manufacturing that is free of ethical concerns. Articular cartilage is commercially available ^[22][39] and its therapeutic potential is well known ^[23][40]. However, resource is limited because only cartilage from child and juvenile donors is effective. The human iPS cell-derived cartilage has characteristics of early developmental stages and is considered more suitable for cartilage repair ^[24][31]. In addition to the above-mentioned projects, clinical trial-oriented research on stem cell therapy for cornea ^[25][26][18,19], heart ^[27][28][20,28], liver ^[29][30][22,29], platelets ^[31][25], spinal cord ^[32][26], immune system (natural killer T cells) ^[33][30], and pancreatic islets ^[34][32] was started. At the time of proposal, the projects using iPS cells were envisioned to use the iPS cells produced from the patient’s own somatic cells such as subcutaneous fibroblasts or lymphocytes. Later, the cell source was changed to the iPS cell stock as mentioned below (see Section 3.3) and all clinical trials are to use allogeneic iPS cells except for Masayo Takahashi’s first trial and Koji Eto’s platelet trial (6_-1 and 11).

3. Social Framework for Clinical Trials of Stem Cell Therapy

3.1. Legislation

Along with the increased support in the research budgets, the adjustment of regulations is important for conducting a national scheme. Previously, only an explanatory clinical run of a cell therapy was allowed, under a decision by the head of the institution in accordance with a report by the institutional review board, which was installed based on national ethics guidelines. At that time, the data were not valid for official investigations of new drugs. In 2014, the revised Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Act No.145 of 10 August 1960) was enacted ^[35][41] and it included two new categories: regenerative medical products and gene therapy products. Regenerative medical products consist of human somatic stem cell- and human somatic cell-processed products at present, because there are no approved products with cells derived from iPS and ES cells. Characteristically, a system of conditional and time-limited approval was introduced for regenerative medical products. The purpose of this system is to apply the products to patients if they are considered to be effective, since it often takes time to determine the effectiveness of regenerative medicine. Once approval or conditional and time-limited approval is given, the medical treatments with the products are covered by health insurance. In 2014, the Act on the Safety of Regenerative Medicine (Act No.85 of 27 November 2013) was enforced ^[36][42]. According to this law, the Ministry of Health, Labor, and Welfare examines all protocols of clinical research on regenerative medicine that had been regulated under national ethics guidelines before. The pancreatic islet transplantation was first performed under this law and after the data estimation was completed, the procedure was authorized and covered by health insurance in 2021, as introduced by Noguchi ^[37][43].

3.2. Japan Agency for Medical Research and Development (AMED)

The Japan Agency for Medical Research and Development (AMED) was established in 2015, as the headquarter that play a central role in the promotion of research and development in the medical field and transition to commercialization ^[38][44]. The budget for clinical-oriented research and development, which had been allocated independently by the Ministry of Health, Labor and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Economy, Trade, and Industry, is now allocated by the AMED. The AMED also maneuvers the approved research projects for their satisfactory execution.

3.3. iPS Cell Stock Project

The advantage of iPS cells in stem cell therapy is the availability of autologous iPS cells, which escape from allogeneic immune rejection. However, the establishment of an iPS cell line is extremely time and cost consuming, especially to establish clinical-grade iPS cell lines that are secured by good manufacturing practice (GMP). Moreover, the acquirement of a successful iPS cell line is affected by individual donor differences, including age. Therefore, the Program of the Research Center Network for Realization of Regenerative Medicine shifted to the use of allogeneic iPS cell lines from tailor-made autologous iPS cells. The iPS cell stock project embarked to produce a collection of iPS cell lines from persons whose human leukocyte antigen (HLA) haplotype is homozygous ^[39][40][41][33,34,35]. As far as HLA-A, HLA-B, and HLA-DR are concerned, the compatibility of those homozygous cells is wider than for heterozygous cells, and 140 homohaplotype lines will cover 90% of the Japanese population ^[41][35]. Although those cells are still allogeneic in minor histocompatibility antigens, the rejection reaction is thought to be mild. Currently, GMP-secured homohaplotype iPS cell lines are used in preclinical studies that are in the middle to late stages when clinical trials are within range.

4. Clinical Trials That Transitioned from Preclinical Projects

All projects with somatic stem cells have started, and some results have been published. The project involving the repair of articular cartilage has four subsidiary trials (1_-1, 1_-2, 1_-3, and 1_-4) from slightly different perspectives. Likewise, the projects involving corneal and liver regeneration have set four and three protocols, respectively. The clinical trials listed here were started after the abovementioned two laws were enacted in 2014, and some similar clinical studies were conducted before then under national ethics guidelines. As for iPS cells and ES cells, 10 out of 13 of the projects have started clinical trials. Although projects with iPS and ES cells are a little behind compared to somatic stem cells, the first-in-human tests are progressing smoothly. The most advanced is the retinal regeneration trial, and the results of two cases with autologous iPS cells (6_-1) and results with five cases using allogeneic iPS cells (6_-2) have already been published ^[42][43][45,46]. The original project was designed with autologous iPS cells, but due to the start of the iPS stock project, the clinical trial shifted toward the use of allogeneic iPS cells. Therefore, the trial with the autologous iPS cells was finished after the completion of the two cases, while the target sample size was five. Another noteworthy clinical trial is the autologous cardiocyte transplantation for neonates with fatal congenital heart disease by Hidemasa Oh at Okayama University Hospital ^[44][53]. His strategy is to return patient’s own cells isolated from tissue that was removed during neonatal cardioplasty to the cardiac tissue. The clinical trials are registered at ClinicalTrials.gov. as the TICAP prospective phase 1, PERSEUS randomized phase 2, APOLLON phase 3 randomized multicenter clinical trial, and the TICAP-DCM study.