RPE and Stem Cell Therapy

acceptedVersionPeer reviewe

MHC-identical and transgenic cynomolgus macaques for preclinical studies

Abstract Cynomolgus macaques are useful experimental animals that are physiologically and genetically close to humans. We have developed two kinds of experimental usage of cynomolgus macaque: transplantation and disease models. First, we identified certain major histocompatibility complex (MHC) haplotypes including homozygotes and heterozygotes in cynomolgus macaques native to the Philippines, because they have less polymorphism in the MHC than that in other origins such as Vietnam and Indonesia. As a preclinical model of the induced pluripotent stem cell (iPSC) stock project, we established iPSCs from various types of MHC homozygous macaques, which were transplanted into compatible MHC heterozygous macaques, the iPSC stock project was experimentally shown to be effective. Second, to obtain disease models of cynomolgus macaques for studies on regenerative medicine including cell therapies, we established two kinds of genetic technology to modify cynomolgus macaques: transgenic technology and gene editing technology using CRISPR-Cas9. We will establish disease models, such as Alzheimer’s disease and progeria (Werner syndrome). In future, we will distribute the MHC-identical cynomolgus monkeys and genetically modified macaques to researchers, especially those engaging in regenerative medicine

A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy

動物由来の成分を含まないより安全な製法でiPS細胞から大量の再生T細胞を培養する方法の開発 --T細胞を使ったがん免疫療法での利用も--. 京都大学プレスリリース. 2021-01-18.Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology