Hepatocytes Encapsulated with mesenchymal stromal cells in alginate microbeads for the treatment of acute Liver failure in Paediatric patients (HELP)

将间充质基质细胞封装在藻酸盐微珠中的肝细胞用于治疗儿科患者的急性肝衰竭（HELP）

• 批准号: MR/V038583/1
• 负责人: Anil Dhawan
• 金额: $ 190.59万
• 依托单位: King's College Hospital
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV038583%2F1
• 关键词: Hepatocytes; Encapsulated; mesenchymal; stromal; cells

Acute liver failure (ALF) is a medical emergency that carries mortality of 80-90% in patients who fulfill liver transplant criteria. Liver transplantation depends on the timely availability of a suitable donor organ and requires life-long immunosuppression with life-threatening complications. Alternatively, the liver has a tremendous regenerative potential: if the failing liver could be supported until regeneration occurs, organ replacement and its associated complications can be avoided. Currently there is no proven liver support device available that can bridge the patient to native liver recovery or to transplant. It has been demonstrated that partial replacement of a patient's liver with a healthy donor liver (called an auxiliary transplantation) can allow clinical stability during native liver regeneration, eventually making the transplanted liver redundant, in up to 70% of the patients. For this, only a small mass of liver tissue is necessary to support the patient. Auxiliary transplant still requires availability of a suitably sized organ, major surgery, and immunosuppression, however. Transplantation of hepatocytes (cells rather than an organ) has been shown to improve synthetic and detoxification function in small animal models with subsequent human application in patients with ALF. The advantages of hepatocyte transplantation in this context are considerable. For example, (i) hepatocytes may be derived from livers which are unsuitable for transplantation; (ii) isolated cells can be frozen for years and used off-the-shelf, something that is impossible with entire organs, thereby eliminating the wait for an appropriate organ; (iii) cells isolated from one liver could treat more than one patient, thereby reducing the need for donor organs; and (iv) this provides options to infants and small children for whom the wait for an appropriately sized organ may be extremely prolonged. Earlier clinical experiences with human hepatocytes in ALF have been only partly successful when cells were injected either in the liver, or the peritoneal cavity, mainly because of rejection and use of immunosuppression in extremely sick patients, which increases the risk of infections. We have developed a technique using liver cells encapsulated in a bio-compatible gel (hepatocyte microbeads - HMB001) that can be infused temporarily in the peritoneal cavity of the patient, to replace the failing liver until regeneration. Importantly, the gel protects the cells from the immune system. The patients therefore do not require immunosuppression. We have previously treated 8 children and infants with HMB001 on a named patient basis (compassionate use). The technique proved to be safe and, importantly, displayed some efficacy: though all children met eligibility for organ transplantation, 4 children recovered with the treatment while awaiting transplant thus entirely avoiding the need for liver transplantation and are still well, up to 8 years after the procedure. We have refined our prototype of hepatocyte microbeads, which now involves multiple cell types and an improved gel that better supports the cell function (HMB002). The new microbeads have shown superior function and longevity in vitro as well as in vivo, in preclinical studies. The aim of this project is to run a clinical trial to test these new microbeads.

急性肝衰竭（ALF）是一种医疗紧急情况，在符合肝移植标准的患者中死亡率为80-90%。肝移植依赖于及时获得合适的供体器官，需要终生免疫抑制，并伴有危及生命的并发症。另一方面，肝脏具有巨大的再生潜力：如果衰竭的肝脏能够得到支持，直到再生发生，器官替换及其相关并发症就可以避免。目前，还没有经过证实的肝脏支持装置，可以桥接病人的天然肝脏恢复或移植。已经证明，用健康的供体肝脏部分替代患者的肝脏（称为辅助移植）可以在原生肝脏再生期间保持临床稳定性，最终使移植的肝脏成为多余的，在高达70%的患者中。为此，只需要一小块肝组织来支持病人。然而，辅助移植仍然需要合适大小的器官、大手术和免疫抑制。在小动物模型中，肝细胞（细胞而不是器官）移植已被证明可以改善合成和解毒功能，随后将其应用于ALF患者。在这种情况下，肝细胞移植的优势是相当大的。例如，(i)肝细胞可能来源于不适合移植的肝脏；（ii）分离的细胞可以冷冻多年并现成使用，这对于整个器官来说是不可能的，从而消除了等待合适器官的时间；（iii）从一个肝脏中分离的细胞可以治疗多个病人，从而减少对供体器官的需求；（iv）这为婴儿和小孩提供了选择，他们等待合适大小的器官的时间可能会非常长。在早期的临床经验中，当将细胞注射到肝脏或腹腔时，ALF患者的肝细胞只取得了部分成功，这主要是因为在病情严重的患者中存在排斥反应和使用免疫抑制，这增加了感染的风险。我们已经开发了一种技术，将肝细胞包裹在一种生物相容性凝胶（肝细胞微珠- HMB001）中，可以暂时注入患者的腹腔，以取代衰竭的肝脏，直到再生。重要的是，这种凝胶可以保护细胞免受免疫系统的攻击。因此，患者不需要免疫抑制。我们之前治疗了8名儿童和婴儿HMB001，以命名患者为基础（同情使用）。这项技术被证明是安全的，重要的是，显示出一定的功效：尽管所有儿童都符合器官移植的资格，但有4名儿童在等待移植的过程中康复，从而完全避免了肝移植的需要，并且在手术后8年仍然很好。我们已经改进了我们的肝细胞微珠原型，现在包括多种细胞类型和一种更好地支持细胞功能的改进凝胶（HMB002）。新型微珠在体外和体内临床前研究中均显示出优越的功能和寿命。这个项目的目的是进行临床试验来测试这些新的微珠。

项目成果

Intraperitoneal transplant of Hepatocytes co-Encapsulated with mesenchymal stromal cells in modified alginate microbeads for the treatment of acute Liver failure in Pediatric patients (HELP)-An open-label, single-arm Simon's two stage phase 1 study protocol.

• DOI: 10.1371/journal.pone.0288185
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7