Pluripotent stem cell derived hepatocytes for liver failure (PUSH for LIFE)

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Liver disease is on the rise. Three quarters of patients are diagnosed at a stage when it is too late for lifestyle changes or medical intervention to make a difference. This results in over 3,000 hospitalized cases and over 40 deaths from liver failure every day in the UK alone. To date, the only cure for a failing liver is to replace the organ with a new one, a procedure called liver transplantation. Unfortunately, we simply do not have enough donor organs to meet the surging demands of patients. Despite performing over 1,000 liver transplants each year, there are still more than 300 people on the transplant waiting list at any one time.Hepatocytes derived from induced pluripotent stem cells (iPSC-Heps) represent a potentially curative alternative, that could replace the need for transplant. We propose to deliver alginate encapsulated iPSC-Heps into the abdomen of patients with liver failure to serve as an auxiliary, short-term liver tissue. In this way, patients will be 'bridged' over the period during which their livers are not working properly until the point at which their liver has sufficiently regenerated to function unaided again or until the point at which a donor organ becomes available. The principle of bridging patients using cell therapy in this way has already been successfully demonstrated in eight patients with cadaveric donor derived primary human hepatocytes (PHH) (Dhawan et al. J. Hepatol. 2020). Due to the scarcity and unpredictable quality of donor PHH, this source of hepatocytes does not however represent a viable long-term solution to address the growing, global unmet medical needs of liver failure. Instead of using PHH therefore, we instead propose to use hepatocytes made from iPSCs. To realise this ambition, we now need to convert our academic iPSC-Hepatocyte generation protocol into a GMP-compliant manufacturing process that allows for the scalable generation of billions of iPSC-Heps which are suitable for patient use.