HIBAL

The goal of the HIBAL project is to propose an innovative treatment of patients with acute liver failure by using a new liver support by combining a high-performance extracorporeal system with a biomass composed of mesenchymal stromal cells and hepatocytes.
Acute liver failure is a devastating condition with up to 30%-50% mortality rate despite advances in critical care and liver transplantation.
At this moment, acellular extracorporeal systems of which the efficacy relies on detoxification modules based on physico-chemical principles (diffusion, convection, adsorption) to purify the blood from toxins and inflammatory factors (MARS®, Prometheus®, and SPAD) are routinely use in clinical practice. Clinical trials have shown a beneficial effect on hepatic encephalopathy, refractory pruritus, renal function, and reduction of cholestasis and jaundice. However, the trials failed to demonstrate a clear beneficial effect on survival.
Consequently, for several years, many bioartificial extracorporeal systems, filled with hepatocytes which are designed to supplement failing liver function have been developed. Recently, a randomized trial of a porcine model of post-hepatectomy liver failure demonstrated that a therapy with a device including porcine hepatocytes was associated with improved survival, reduced ammonia levels, and accelerated liver regeneration. These promising results confirm the relevance of this latter therapeutic choice and suggest that there is potential for further improvement. However, they also raise concerns about the source of the biomass, as regulations severely restrict the use of pig cells, and their use is banned in several European countries.
Acute liver failure is characterized by an important deficit of liver function but also by an inflammatory process due to the tissue degradation that leads not only to the local release of inflammatory cytokines, chemokines, and ligands by non-parenchymal cells, such as Kupffer cells, hepatic stellate cells, and various immune cells but also to an overflow of DAMP molecules into the systemic circulation. These molecules activate monocytes and macrophages resulting in further release of pro-inflammatory cytokines and reactive oxygen and nitrogen. Mesenchymal stromal cells via various soluble factors and extracellular vesicles, suppress the immune response, modulate inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, regress liver fibrosis, and improve liver functionality. Consequently, we propose to develop a new model of liver support that meets clinical standards by combining a high-performance extracorporeal system with an innovative biomass composed of mesenchymal stromal cells and hepatocytes derived from the same clone of induced pluripotent stem cells thanks to the well-known expertise of the teams involved.
To achieve this objective, we will

1. produce a large hepatic and mesenchymal cells biomass capable of meeting clinical standards (GMP) from the same GMP-grade human induced pluripotent stem cell (hiPSC) line,
2. design a new extracorporeal system capable of meeting clinical standards,
3. conduct a proof of concept in a porcine model of chemically induced acute liver failure.

The HIBAL project, with its innovative approach and strategic collaborations, represents a unique opportunity to strengthen France’s position in the field of liver support and effectively meet current and future clinical needs.