Dr. Tamir Rashid PhD, MRCP MRC Clinician Scientist Fellow, Senior Lecturer & Honorary Consultant Hepatologist, KCL 2014 AEEH Meeting, Madrid: Induced Pluripotent Stem Cells for treatment of liver disease

Conflict of interest declaration Scientific founder of Definigen Ltd - consultancy & shares

Overview Reprogramming factors Patient

 1 -antitrypsin deficiency (Z) 342 Glu to Lys PolymerisationHepatic accumulation Disease Lomas & co-workers;

Only ‘curative’ treatment to date Whole organ transplantation

Liver transplantation 1.Short term – 10% operative risk 2.Long term - Immune suppression related morbidity 3.Big Challenge – donor shortage Thomas Starzl Roy Calne

Alternative to whole organ transplant? vs.

Cell therapy Ding, Roy Chowdhury et al JCI 2011

Acute liver failure 37 patients Chronic Liver disease 20 patients Metabolic liver disease 21 patients

Cell therapy - problem 1: Quantity Liver =1.5kg in weight (15% blood) 4 x 10 9 cells per kg 5 % cell replacement for metabolic recovery If engraftment efficiency is 5% Need 1 x cells (billions)

Cell therapy - problem 2: Quality Source of cells Need for storage Immunosuppression

Pluripotent stem cells Cell clumps hESCs Thompson (1998) iPSCS Somatic cells. (Skin Cells) Oct-4 / Sox2 / Klf4 / C-Myc Yamanaka (2006) 1.Unlimited numbers 2.Any cell 3.Patient specific 4.Autologous 5.Less ethical concerns

Reprogramming patient skin samples Banito, Rashid et al., Genes Dev 2009 Reprogramming factors

Turning patient skin derived hiPSCs into liver cells Rashid et al., J Clin Invest 2010