BALANCE

Development of a bioartificial liver therapy in acute liver failure

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 Obiettivo del progetto (Objective)

'In BALANCE, the companies Hep-Art, Pharmacell and BioPredic join forces with academic partners Amsterdam Medical Centre and University of Edinburgh to offer Acute Liver Failure (ALF) patients a bioartificial liver-support system for bridging the waiting period for liver transplantation or recovery of the diseased liver. ALF is a highly lethal disorder and liver transplantation is the only life-saving therapy. However, limited availability of donor livers severely reduces its impact. A bioartificial liver (BAL) may support ALF patients by temporary and extracorporeal treatment of their plasma through a bioreactor with functional human liver cells. The central objective of BALANCE is to develop a HepaRG-BAL that executes the three key liver functions for a clinically relevant period in ALF and to reach proof of safety and feasibility. What makes the HepaRG-BAL extremely potent is the unique combination of an ideal liver cell ecosystem and the introduction of the HepaRG cell line which is the only human cell line in the world that approaches human liver in its functionality. A two-staged approach will be adopted. Stage I is designed for in-vitro optimisation of the BAL and the human cell line and stage II comprises of the ex-vivo activities in which the optimized and upscaled BAL is tested and validated in pigs (controlled study). In addition approvement of a Phase I/IIa in humans will be prepared. . BALANCE will give birth to four main results: an optimised and validated BAL, a large scale manufacturing process, proof of concept in a large animal model of ALF and basic information for regulatory approval for future clinical application. Hep-Art will further pursue clinical development of the BAL towards EMA registration and marketing together with a large industrial partner. BioPredic will further exploit the HepaRG cells. Last but not least, BALANCE will strengthen the European competitive advantage in the field of bioartificial organs.'

Descrizione progetto (Article)

A BAL is a bioreactor loaded with embedded liver cells. This extracorporeal supportive device temporarily replaces liver function. Pre-clinical experiments have shown the effectiveness of BAL systems. However, previous clinical trials failed to show survival benefit mainly due to the use of unstable cells with low functionality.

The EU-funded 'Development of a bioartificial liver therapy in acute liver failure' (http://fp7balance.eu/ (BALANCE)) consortium are developing and optimising a new cell system to increase patient survival. The ideal BAL is based on human cells that mimic functioning of a normal human liver. It has to execute three key tasks: detoxification, hepatic synthesis and hepatic regulation of homeostasis. HepaRG is the only human cell line in the world that is able to carry out these key tasks.

The BAL has a unique internal matrix on which more than ten billion cells can be seeded. Due to the composition of the matrix and the use of fibres for oxygen supply and carbon dioxide removal, the cells organise as 3D liver-like tissue.

Master cell banks of the HepaRG cell line were prepared and tested for safety and functionality during passaging or subculture. The HepaRG cells were functionally stable until passage 20 and demonstrated a stable slightly abnormal karyotype up to passage 22. Potential tumourigenicity of the cells is currently under investigation in standard tests.

Microcarrier-based bioreactor cell culture screening was investigated. Several test runs were performed to define settings such as seeding density, harvesting optimisation and microcarrier density.

An appropriate non-human clinical model was successfully developed. The production of the BAL hardware system has been designed, manufactured, validated and finalised.

The potential impact of an effective BAL system on healthcare is immense. In the future it could offer thousands of patients a better outlook in terms of surviving severe liver failure.