Hypoimmune editing of iPSC-derived cell therapies

In 2006, Shinya Yamanaka and colleagues made the groundbreaking discovery that differentiated cells can be reprogrammed back to a pluripotent state that enables the differentiation of an unlimited amount of any cell type needed for therapeutic purposes. These cells, termed iPSCs, have become the basis of a new field of regenerative medicine and led to countless applications in regenerative medicine, drug testing and disease modelling. iPSCs have the advantage of being able to develop into over 200 human cell types. For example, iPSCs can be made to develop into neural tissues to treat Parkinson’s Disease or into pancreatic cells to treat diabetes. Moreover, the function of iPSCs can be enhanced through genome editing. Persistence of iPSC-derived cell therapies is hampered by immune attack of therapeutic cells from the host immune system. To overcome these obstacles, investigators have deleted B2M and CIITA, which are critical for expression of MHC Class I and II respectively. However, cells lacking MHC class I are subject to NK cell attack due to “missing self” antigens. To overcome this, it is possible to overexpress certain “don’t eat me” factors that prevent NK cell attack. In this project, we will simultaneously delete B2M and CIITA whilst giving simultaneous high-level expression of factors that prevent attack by NK cells. We will test the ability of these cells to avoid immune attack and allow durable engraftment of iPSC-derived cells in therapeutic models. This project will utilise advanced technologies in iPSC reprogramming, genome editing and cell differentiation, along with techniques for characterisation of iPSCs (genome, gene expression and epigenetic analyses) and differentiated cells (immunocytochemistry, flow cytometry, in vitro and in vivo assays of cell function).