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

肝病的发病率正在上升。四分之三的患者是在生活方式改变或医疗干预无法起作用的时候被诊断出来的。仅在英国，每天就有3000多例住院病例和40多例死于肝功能衰竭。到目前为止，治疗衰竭肝脏的唯一方法是用一个新的器官替换这个器官，这一过程被称为肝移植。不幸的是，我们根本没有足够的捐赠器官来满足患者激增的需求。尽管每年进行1000多例肝脏移植，但在任何时候仍有300多人在等待移植。来自诱导多能干细胞的肝细胞(IPSC-HEPs)是一种潜在的治愈替代方案，可以取代移植的需要。我们建议将藻酸盐包裹的ipSC-Heps送入肝功能衰竭患者的腹部，作为辅助的短期肝组织。通过这种方式，患者将在肝脏无法正常工作的这段时间内被“桥接”，直到他们的肝脏充分再生，可以在没有辅助的情况下再次发挥功能，或者直到可以获得供体器官。以这种方式使用细胞疗法桥接患者的原理已经在8名身体供者来源的原代人类肝细胞(PHH)患者中得到成功证明(Dhawan等人)。J.肝醇。2020)。然而，由于供体PHH的稀缺性和不可预测的质量，这种肝细胞来源并不代表一个可行的长期解决方案来解决日益增长的、全球未得到满足的肝功能衰竭的医疗需求。因此，我们建议使用IPSCs制成的肝细胞，而不是使用PHH。为了实现这一雄心壮志，我们现在需要将我们的学术IPSC-肝细胞生成协议转换为符合GMP的制造工艺，以允许可扩展地生成适合患者使用的数十亿IPSC-HEP。

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.