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

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.

Acute liver failure (ALF) in children and adults is a rare disease with high mortality without liver transplantation (LTx), as other therapies like extracorporeal liver assist devices have failed to demonstrate efficacy. LTx is life saving but limited by the scarcity of donor organs. In addition, life-long immunosuppression needs make liver transplant itself another disease. Success of auxiliary liver transplantation, demonstrating more than 70% native liver recovery, suggests that few weeks of support with minimally invasive hepatocytes microbeads could provide similar outcome to auxiliary liver transplant in children with ALF of diverse aetiologies. We have proven the feasibility and safety of the transplantation of human hepatocyte microbeads (HMB001) for the treatment of ALF in children, and the partial success of this approach, supported by a NIHR grant. In the last few years, further supported by the NIHR, we have developed HMB002, made of primary human hepatocytes and support cells encapsulated in a novel alginate. HMB002 showed greater function and longevity than HMB001: after 14 days, in vitro albumin production was 60x higher in HMB002 than in HMB001 and the A1AT production 32x higher. In vivo data showed a similar pattern, leading us to believe that HMB002 would be more potent in providing effective liver support to bridge the patients to recovery without liver transplantation, or bridge them to liver transplantation.
The i4i NIHR grant allowed us to develop HMB002 as a GMP (ATIMP) clinical product. Our clinical trial application was awarded MHRA approval in September 2020.
The aim of this project is to undertake a phase I/II clinical trial to test HMB002 in children with ALF to assess its safety/efficacy. Success of this trial would open a road to commercialisation with consideration of extended use to treat adults with ALF and bridge patients with acute-on-chronic liver failure to liver transplantation.