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，满足肝移植标准的患者死亡率为 80-90%。肝移植取决于能否及时获得合适的供体器官，并且需要终生免疫抑制并伴有危及生命的并发症。另外，肝脏具有巨大的再生潜力：如果能够支持衰竭的肝脏直至再生，就可以避免器官置换及其相关并发症。目前，还没有经过验证的肝脏支持装置可以帮助患者实现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）可以在天然肝脏再生过程中实现临床稳定性，最终使高达 70% 的患者的移植肝脏变得多余。为此，只需要少量的肝组织来支持患者。然而，辅助移植仍然需要适当大小的器官、大手术和免疫抑制。肝细胞（细胞而不是器官）移植已被证明可以改善小动物模型的合成和解毒功能，并随后应用于人类 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)肝细胞可以源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，从而消除了对合适器官的等待； (iii) 从一个肝脏中分离出的细胞可以治疗多名患者，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，因为他们等待合适大小的器官的时间可能会非常长。早期的人类肝细胞治疗 ALF 的临床经验仅在将细胞注射到肝脏或腹膜腔时取得部分成功，这主要是因为病情严重的患者出现排斥反应和使用免疫抑制剂，这增加了感染的风险。我们开发了一种技术，使用封装在生物相容性凝胶（肝细胞微珠 - HMB001）中的肝细胞，可以将其暂时注入患者的腹膜腔中，以替代衰竭的肝脏直至再生。重要的是，凝胶可以保护细胞免受免疫系统的侵害。因此，患者不需要免疫抑制。我们之前已以指定患者为基础（同情使用）使用 HMB001 治疗了 8 名儿童和婴儿。该技术被证明是安全的，而且重要的是，显示出一定的疗效：尽管所有儿童都符合器官移植的资格，但 4 名儿童在等待移植期间通过治疗康复了，从而完全避免了肝移植的需要，并且在术后 8 年内仍然状况良好。程序。我们改进了肝细胞微珠的原型，现在涉及多种细胞类型和改进的凝胶，可以更好地支持细胞功能（HMB002）。在临床前研究中，新型微珠在体外和体内均显示出卓越的功能和较长的使用寿命。该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

Outbreak of hepatitis in children: clinical course of children with acute liver failure admitted to the intensive care unit.

• DOI: 10.1007/s00134-022-06765-3
• 发表时间: 2022-07
• 期刊: INTENSIVE CARE MEDICINE
• 影响因子: 38.9
• 作者: Deep, Akash;Grammatikopoulos, Tassos;Heaton, Nigel;Verma, Anita;Dhawan, Anil
• 通讯作者: Dhawan, Anil

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