Overview of the iPSC stock project
iPSCs have the ability to self-renew and differentiate into all cell types of the human body, and their practical application is expected to be realized in the near future [1, 2]. There are two approaches to iPSC-based cell transplantations: autologous and allogeneic. Autologous transplantation is a procedure in which target cells/tissues derived from an individual’s own iPSCs are transplanted into the self. In contrast, allogeneic transplantation uses iPSC-derived target cells/tissues donated by a third person for the transplantation.
Autologous transplantation is preferable in order to avoid immune reactions and unknown virus infections. However, it is extremely costly, and the time required to prepare and transplant the target cells/tissues can be unacceptably long medically. In September 2014, for the world’s first iPSC-based therapy, the autologous transplantation of iPSC-derived retinal pigment epithelium (RPE) cells required the patient to wait over 10 months for the surgery and cost nearly 100 million yen (approximately US $1 million) [3]. With an allogeneic approach, a sufficient number of iPSCs can be generated and comprehensive quality testing can be performed in advance, which can help reduce the cost and time of the iPSC manufacturing process.
However, immune rejection remains an issue in allogeneic transplantation. HLA antigens have been known to play an important role in immune responses. In hematopoietic stem cell transplantation (HSCT), HLA matching between donors and recipients lowers the risk of graft rejection and graft-versus-host disease (GVHD). Moreover, for some organ transplantations, HLA matching has been shown to enhance allograft survival in adults who receive an organ from either a deceased or living donor. Following these models, we are screening healthy donors with homozygous human leukocyte antigen (HLA)-A, HLA-B, and HLA-DR to establish our iPSC stock. Based on previous works [4, 5], it is estimated that 10, 75, and 140 cell lines would match approximately 50%, 80%, and 90% of the Japanese population, respectively.
We have released clinical-grade iPSCs from the stock, including three lines from peripheral blood mononuclear cells (PBMCs) with first-, second-, and third-ranked HLA haplotypes and two lines from cord blood with first-ranked HLA haplotypes at the Facility for iPS Cell Therapy (FiT), a cell-processing center (CPC) at the Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan. These three haplotypes cover approximately 32% of the Japanese population. One study using cells from our iPSC stock showed the effectiveness of this strategy in non-human primates [6]. Accordingly, cells from the stock were used in the first iPSC-related allogeneic transplantation, which also used RPE cells and followed the same procedure as the above autologous transplantation. The surgery time was shortened to about 1 month, and the overall cost was under 20 million yen per patient [7]. However, despite these encouraging results, the overall utility of regenerative medicine with HLA matching needs more investigation [8,9,10].