Centre de Référence Maladies Rares


Biotherapy of genetic diseases, inflammatory disorders and cancers (BMGIC)

FR: Biologie Fondamentale Appliquée à la Médecine

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Biotherapy team
Project 1.3

Hepatocyte differentiation from human iPSCs: physiopathological studies and therapeutic applications for inherited liver diseases

keywords: iPSC, hyperoxaluria, gene therapy


Transplantation of allogenic or genetically modified autologous hepatocytes may be an alternative to whole-liver transplantation for the treatment of inherited liver diseases (ILD). Several aspects can actually limit the clinical use of hepatocyte transplantation such as poor in vitro amplification, limited engraftment of transplanted hepatocytes in vivo, and the necessity for immune suppression (allogenic graft). Furthermore, relevant ILD-patients-specific models of hepatocytes would strongly enhance our knowledge of the pathophysiological mechanism responsible for ILD. In this project, we propose to generate induced pluripotent stem cells (iPSCs) from patients with primary hyperoxaluria type-1 (PH1). PH1 is an inherited disorder due to alanine-glyoxylate-amino transferase (AGT) deficiency and characterized by overproduction of oxalate by the liver leading to sever nephrocalcinosis, nephrolithiasis and end-stage renal failure. PH1-iPSCs-derived hepatocytes would represent faithfully models to support pathophysiological studies and therapeutic drug screening. We will also evaluate a targeted gene therapy approach in PH1-iPSCs-derived hepatocytes using TALEN-mediated gene correction at the endogenous human AGXT locus. This strategy would offer a safe and broad genetic correction together with physiological regulation of the therapeutic transgene. A similar approach is considered for acute hepatic porphyrias to develop patient-specific hepatocytes as models for porphyrinogenic drug screening. Our goal is to improve the development of iPSCs-derived hepatocytes as valuable models of ILD and develop new therapeutic approaches in regenerative medicine.

Related publications:

  • Generation of induced pluripotent stem cells-derived hepatocyte-like cellsforexvivogene therapy of primary hyperoxaluria type 1. Julie Estève*, Jean-Marc Blouin*, Magalie Lalanne, Lamia Azzi-Martin, Pierre Dubus, Audrey Bidet, Jérôme Harambat, Brigitte Llanas, Isabelle Moranvillier, Aurélie Bedel, François Moreau-Gaudry, Emmanuel Richard. * contributed equally Stem Cell Research () 31151050

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