The development of 3-dimensional implantable liver organoids

Liver disease is the 5th most common cause of death in the UK. 16,087 people in the UK died from liver disease in 2008, a 4.5% increase since 2007 and trends are rising. Liver disease kills more people than diabetes and road deaths combined. The only curative option for end-stage cirrhosis and acute liver failure is liver transplantation, however organ availability cannot meet demand and many patients die waiting for an organ. Those who undergo transplantation require lifelong treatment with increased risks of infection, cancer, kidney and heart disease. Thus, there is a clear need to identify alternatives to liver transplantation. Recent studies have shown that human cells can small fragments of liver like tissue. While providing proof of concept, the tissue is very small and lacks key liver functions. To address this we have assembled a team with complementary expertise to reliably produce human liver tissue with clinically relevant function.

Liver disease is the 5th most common cause of death in the UK. 16,087 people in the UK died from liver disease in 2008, a 4.5% increase since 2007 and trends are rising. Liver disease kills more people than diabetes and road deaths combined (REF: Office for National Statistics: Health Service Quarterly, Winter 2008, No. 40 p59-60). The only curative option for end-stage cirrhosis and acute liver failure is liver transplantation, however organ availability cannot meet demand and many patients die waiting for an organ. Those who undergo transplantation require lifelong immunosuppression with concomitant risks of infection, cancer, renal and cardiovascular disease. Thus, there is a clear imperative to identify alternatives to liver transplantation. Recent studies have shown human pluripotent stem cells (hPSC) co-cultured with MSCs and endothelial cells can form primitive liver organoids (Takebe et al. Nature 2013). While providing proof of concept the in vitro derived spheroids are tiny and lack a functional biliary system, requiring transformative innovation before they can be used clinically. To deliver this we have assembled a team with complementary expertise in the production and use of stem cell derived hepatocyte and cholangiocytes-like cells, hepatocyte niche construction, three-dimensional scaffold production and in vivo modelling. This collaborative group includes scientists and clinicians with experience in human cell production, GMP cell production and clinical cell therapy for liver disease. This group is ideally placed to translate these pre-clinical observations into a therapy for patients with liver failure or metabolic liver diseases, and particularly the use of liver buds derived from genetically corrected iPS cells in the case of liver disease caused by single gene defects.

This project will develop the technology needed to help advance the treatment of human liver disease by providing implantable devices for liver support. We envisage clinical utility in 4 settings:
(a) Where acute liver injury had occurred (drug-induced or post-hepatectomy) and this liver support would support the patient until endogenous repair had occurred,
(b) In acute on chronic liver failure where the patient has been listed for transplantation but no suitable organ is immediately available- the aim would be to stabilise and support the patient until a suitable donor organ is available
(c) As rescue therapy in paediatric cases of inborn errors of liver metabolism where the lack of specific proteins in the patient hepatocytes can lead to multiple organ failure.
(d) The ability to model human disease 'in a dish' has revolutionary potential for new and safer drug design to treat liver disease and tissue regeneration.
The changeable genetic element within our system will allow for the tissue to be tailor-made for the recipient, obviating the need for immunosuppressive drugs (and their side effects). This type of disruptive technology will bolster economic development within the UK and maintain our position as a world leader in our respective scientific fields. Such improvements will have significant benefits in terms of direct and indirect healthcare costs, social and welfare costs. In addition, by addressing an unmet medical need, the project has a great potential for wealth creation for the UK. To develop the impacts we shall engage:
(i) Clinical practitioners and transplant surgeons
The consortium has strong clinical focus. Engagement with the relevant clinical practitioners and transplant surgeons has already been established. SJ Forbes, A Dhawan and PN Newsome are clinicians within 3 large UK liver transplant units covering both adult and paediatric liver patients.
(ii) Cell based modeling to develop safer and new medicines
The consortium has built up a strong relationship with industry and is well positioned to deliver novel models for application. The benefits for the industry have the potential to be realised within only a few months of completion of the project. Academic research groups could also utilise the technology within a similar time frame.
(iii) Government / Regulatory Authorities
The introduction of new treatments for liver disease or screening models will lead to the development of novel medicines, which will be managed in consultation with regulatory authorities that oversee drug safety, efficacy and cost. We have engaged with the Cell Therapy Catapult who see the merit of our application and have provided a letter of support.