Final Report Summary - RELIEVE-IMDS (Reprogramming cell identity to develop new therapies against Inherited Metabolic Disorders of the liver)
Liver diseases are becoming one of the most common causes of mortality in developing countries, and liver transplantation is the only available treatment. However, this procedure carries considerable risk and also implies indefinite immunosupression treatment associated with heavy side effects and eventual rejection. Furthermore, an increasing number of patients die while on the liver transplant waiting list due to the shortage of suitable donor livers. Hepatocyte represent the main functional cell type of the liver and their transplantation recently became an alternative to liver transplantation for the treatment of life-threatening Inherited Metabolic Diseases of the liver. However, this cell based therapy has also been hampered by the lack of donors and by the difficulty in growing primary hepatocytes in vitro. Therefore, developing alternative source of hepatocytes remains a major goal in the regenerative medicine field. Pluripotent stem cells generated from reprogrammed somatic cells (human Induced Pluripotent Stem Cells or hIPSCs) represent an advantageous solution since they can proliferate indefinitely in vitro while maintaining their capacity to differentiate into a broad number of cell types including hepatocytes. In addition, hIPSCs could enable the production of patient specific cell types which are fully immuno-compatible with the original donor thereby avoiding the need for immune suppressive treatment during cell based therapy. For all these reasons, hIPSCs represent a unique opportunity for the development of cell based therapies against liver diseases. he objective of the Relieve-IMDs program of research was to systematically address the limitations preventing utilization of hIPSCs in the context of cell based therapies against liver disease. We first developed a new approach for generating hIPSCs from blood cells and then validate the compatibility of the resulting cell lines with clinical applications. We also improved protocol to differentiate hIPSCs into fully functional adult hepatocytes and develop a diversity of protocols for the production of alternative cell types such a lung, pancreas, lung and biliary cells. In parallel, we have established method to edit the mammalian genome in order to correct genetic defects involved in specific inherited liver disease. Finally, we have validated the safety of hIPSCs derived hepatocytes in vivo using animal model for liver disease. Combined together these results provides the first steps toward the development of new cell therapies against liver disease.