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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
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Conflict of interest declaration
• Scientific founder of Definigen Ltd - consultancy & shares
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Overview
Reprogramming factors
Patient
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1-antitrypsin deficiency (Z)
342Glu to Lys Polymerisation Hepatic accumulation Disease
Lomas & co-workers; 1990-2012
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Only ‘curative’ treatment to date
Whole organ transplantation
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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
641668
637 636
706686
647
712
676
611
688
632
675679
633 657
600
705661 649
516
374
338
268314
365
264
190175202
0
100
200
300
400
500
600
700
800
900
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
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Alternative to whole organ transplant?
vs.
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Cell therapy
Ding, Roy Chowdhury et al JCI 2011
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Acute liver failure 37 patients
Chronic Liver disease 20 patients
Metabolic liver disease 21 patients
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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)
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Cell therapy - problem 2: Quality
• Source of cells• Need for storage• Immunosuppression
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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
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Reprogramming patient skin samples
Banito, Rashid et al., Genes Dev 2009
Reprogramming factors
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Turning patient skin derived hiPSCs into liver cells
Rashid et al., J Clin Invest 2010