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

多能干细胞衍生的肝细胞治疗肝衰竭（PUSH for LIFE）

• 批准号: MR/Z503940/1
• 负责人: Tamir Rashid
• 金额: $ 31.33万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ503940%2F1
• 关键词: Pluripotent; stem; cell; derived; hepatocytes

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.

肝脏疾病呈上升趋势。四分之三的患者在确诊时已为时已晚，无法改变生活方式或进行医疗干预。仅在英国，每天就有超过 3,000 例住院病例和超过 40 例因肝功能衰竭死亡。迄今为止，治疗衰竭肝脏的唯一方法是用新器官替换该器官，这种手术称为肝移植。不幸的是，我们根本没有足够的捐献器官来满足患者不断增长的需求。尽管每年进行 1,000 多例肝移植，但每次仍有超过 300 人在等待移植名单上。源自诱导多能干细胞 (iPSC-Heps) 的肝细胞代表了一种潜在的治疗替代方案，可以取代对肝移植的需求。移植。我们建议将藻酸盐封装的 iPSC-Heps 输送到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，患者的肝脏不能正常工作的时期将得到“弥补”，直到他们的肝脏充分再生以在无需帮助的情况下再次发挥作用，或者直到可以使用供体器官为止。以这种方式使用细胞疗法来桥接患者的原理已在 8 名使用尸体供体来源的原代人肝细胞 (PHH) 的患者中成功得到证实 (Dhawan et al. J. Hepatol. 2020)。然而，由于供体 PHH 的稀缺性和质量不可预测，这种肝细胞来源并不代表解决全球不断增长的、未满足的肝衰竭医疗需求的可行的长期解决方案。因此，我们建议使用由 iPSC 制成的肝细胞，而不是使用 PHH。为了实现这一目标，我们现在需要将我们的学术 iPSC-肝细胞生成协议转化为符合 GMP 的制造流程，从而能够大规模生成适合患者使用的数十亿个 iPSC-Heps。