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

急性肝功能衰竭(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。或者，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，器官替换及其相关的并发症就可以避免。目前还没有经过验证的肝脏支持设备可以将患者连接到自然肝脏恢复或移植。已经证明，用健康的供体肝脏部分替换患者的肝脏(称为辅助移植)可以在自然肝再生期间保持临床稳定性，最终在高达70%的患者中使移植肝脏变得多余。为此，只需要一小块肝组织来支持患者。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。肝细胞移植(细胞而不是器官)已被证明可以改善小动物模型的合成和解毒功能，随后人类将其应用于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)肝细胞可能来自不适合移植的肝脏；(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，从而消除了对适当器官的等待；(Iii)从一个肝脏分离的细胞可以治疗不止一个患者，从而减少对捐赠器官的需求；以及(Iv)这为等待适当大小的器官的婴儿和幼儿提供了选择。早期在ALF中使用人类肝细胞的临床经验只有部分成功，当细胞被注射到肝脏或腹膜腔时，主要是因为排斥反应和重症患者使用免疫抑制剂，这增加了感染的风险。我们已经开发出一种技术，使用生物兼容凝胶(肝细胞微珠-HMB001)包裹的肝细胞，可以暂时注入患者的腹膜腔，以取代衰竭的肝脏，直到再生。重要的是，这种凝胶保护细胞免受免疫系统的攻击。因此，患者不需要免疫抑制。我们之前已经治疗了8名儿童和婴儿HMB001在指定患者的基础上(同情地使用)。事实证明，这项技术是安全的，重要的是，显示了一些效果：尽管所有儿童都符合器官移植的条件，但有4名儿童在等待移植期间通过治疗康复，从而完全避免了肝移植的需要，而且在手术后长达8年的时间里仍然很好。我们已经改进了我们的肝细胞微珠原型，现在涉及多种细胞类型和一种更好地支持细胞功能的改进凝胶(HMB002)。在临床前研究中，新的微球在体外和体内都表现出了优越的功能和寿命。该项目的目的是进行临床试验，以测试这些新的微珠。

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.