PhD Training Programme for Clinicians at the University of Cambridge: 'Generation of patient specific stem cells towards cell based therapy of inherited metabolic diseases of the liver'. (360G-Wellcome-087006_Z_08_Z)

To evaluate the potential of patient specific induced pluripotent stem cell (iPSC) derived hepatocytes to generate cells for cell transplant therapy in treating inherited metabolic diseases of the liver, a new chimeric mouse - human diseased liver model will be created. The first step will involve taking hepatocyte / skin fibroblast cells from Alpha 1 Antitrypsin deficient patients and reprogramming them in vitro to iPSCs. These cells will then be differentiated to hepatic progenitors and used to repopulate the liver of the FAH-/- mouse to produce a novel chimeric mouse - human liver model. The same patient specific iPSC derived hepatocytes will be genetically corrected and engrafted into the mouse model to try and achieve functional correction of the disease phenotype. By this we aim to 1) produce a new human hepatocyte cell line for Alpha 1 Antitrypsin deficiency 2) produce a new chimeric mouse - human liver 3) produce a new patient specific corrected human hepatocyte cell line from (1) 4) show proof of principle that engrafting the corrected cell line could be a therapeutic strategy towards treatment of A1ATD and other inherited metabolic disorders of the liver.