Progress towards the CGMP production of pluripotent stem cell derived red blood cells

      Blood transfusion is a wide spread and important clinical intervention, however problems persist both nationally and internationally in maintaining adequacy of supply, managing the risk of transmission of infectious agents and immune incompatibility between donor and recipient. Human embryonic and induced pluripotent stem cells (hESCs & hiPSC) have unique properties in that they can be maintained indefinitely in culture in an undifferentiated state and yet retain the ability to form all the cells and tissues within the body. They therefore offer a potentially scalable source from which to generate red cells (RBCs) for use in clinical transfusion. We have evaluated hESC lines derived under Good Manufacturing Practice (GMP) conditions in compliance with UK regulatory requirements for clinical products and are preparing master cell bank stocks of the lead line for clinical use, RC9. We are able to differentiate these RC9-hESCs to form haematopoietic progenitor cells (HPC) which subsequently result in ≥95% conversion to erythroid cells (GlyA+, CD45-, haemoglobinised) with up to 350,000 fold expansion in cell numbers, in a stroma-free, animal product-free suspension based culture system. The culture process starts with a short embryoid body stage followed by sequential changes in inductive cytokines and growth factors taking up to 30 days. We have also demonstrated that this methodology is similarly effective for hiPSC. The erythroid cells express foetal (alpha/gamma) rather than embryonic (epsilon/zeta) haemoglobin and achieve reasonable enucleation. Many challenges exist in taking this product through to clinical trial including optimisation of the differentiation an maturation protocol, scale-up and optimisation of process control in manufacturing, cGMP-translation and cost-control, and the regulatory and commercial challenges of moving through to first in man clinical studies.
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