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。四分之三的患者被诊断时，生活方式的改变或医疗干预已经为时已晚。仅在英国，每天就有3000多例肝功能衰竭住院，40多例肝功能衰竭死亡。到目前为止，治疗肝脏衰竭的唯一方法是用一个新的器官代替，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。尽管每年进行的肝移植手术超过1000例，但任何时候都有300多人在等待移植。诱导多能干细胞（iPSC-Heps）衍生的肝细胞代表了一种潜在的治疗选择，可以取代移植的需要。我们建议将海藻酸盐封装的iPSC-Heps注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，患者将在肝脏不能正常工作的一段时间内被“桥接”起来，直到他们的肝脏能够充分再生，能够在没有帮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例尸体供体来源的原代人肝细胞（PHH）患者中得到成功证明（Dhawan等）。国际肝病杂志，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种可行的长期解决方案，以解决日益增长的全球未满足的肝衰竭医疗需求。因此，我们建议使用由iPSCs制成的肝细胞代替PHH。为了实现这一目标，我们现在需要将我们的学术ipsc -肝细胞生成方案转化为符合gmp的制造工艺，以允许可扩展地生成数十亿个适合患者使用的iPSC-Heps。