dr. tamir rashid phd, mrcp mrc clinician scientist fellow, senior lecturer & honorary consultant...

Dr. Tamir Rashid PhD, MRCP

MRC Clinician Scientist Fellow, Senior Lecturer & Honorary Consultant Hepatologist, KCL

tamir.rashid@kcl.ac.uk

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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676

611

688

632

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633 657

600

705661 649

516

374

338

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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

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