dr. tamir rashid phd, mrcp mrc clinician scientist fellow, senior lecturer & honorary consultant...
TRANSCRIPT
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)
342Glu to Lys Polymerisation Hepatic accumulation Disease
Lomas & co-workers; 1990-2012
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
Source: Transplant activity in the UK, 2010-2011, NHS Blood and Transplant
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2001-2002 2002-2003 2003-2004 2004-2005 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011
Year
Num
ber
Donors
Transplants
Transplant list
Deceased donor liver programme in the UK, 1 April 2001 - 31 March 2011Number of donors, transplants and patients on the active transplant list at 31 March
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 10 10 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 cell3. Patient specific4. Autologous5. 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