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A Rahman A Jamal MD, MRCP, PhD, PJN, DPNS, ANS
Director
UKM Medical Molecular Biology Institute
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Heart-rending stories:
Stem cells giving hope to patients
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The promise of stem cells:
A cure for many diseases
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Stem cell research:
Latest advances
Controllingself-renewal &differentiation
Programmingsomatic cells
into stem cells
Makingembryos from
stem cells
Clinicalapplications
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1. Controlling stem cells:A chemical switch for mass production
Proliferation Differentiation
Hydrogel (rich in alginate)
Cells become collagen-richwhen the population becomesbig enough
Dixon et al, PNAS, 2014
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Manipulating the microenvironment:
ECM with autologous proteins
The autologous ECM proteins were then used to culture and expand hESc cells
Khoo et al. (2013) Differentiation.85(3):110-8
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SSEA-4 TRA-1-81 Nuclei SSEA-1 Merged
Oct4 Nuclei Merged
SSEA-3 Nuclei Merged
Khoo et al. (2013) Differentiation.85(3):110-8
Manipulating the microenvironment
to maintain pluripotency
Human embryonic stem cells (hESc) grown on extracellular matrix (ECM)
retained its pluripotency after more than 1 year in culture
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Breakthrough technique
to culture foregut stem cells
A culture system to isolate
foregut stem cells
Thyroid, upper airways, lungs, liver,pancreas, stomach and biliary systems
Vast applications to culture cells forregenerative medicine
Hannan et al, Stem Cell Reports, 2013
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2. Reprogramming somatic cells
into stem cells
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Improved efficiency of
re-programming cells
Yamanaka method
Turning skin cells
into iPSCs 4 genes
Low efficiency (
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3. Making embryos
from stem cells
Zebrafishembryo
Nodal BMP
Thisse et al, Science, 2014
Embryonic stem cellssubjected togrowth factor signals
Implications:Therapeutic cloning
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4. Clinical application:
Ischaemic Heart Disease Ischaemic heart
disease
23 RCTs 1200 patients
Reduced deaths andreadmission
Quality ofevidence is lowbecause of low
numbers
Implications
Need larger clinical
trials Need better
understanding ofthe cells used
Need to study theirmechanism ofaction
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Beneficial but low quality evidence
Fisher et al, Cochrane Reviews 2014
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The regulation of stem cells:
Ethical issuesEmbryos
SC for unprovenindications
Mechanism ofaction
Stem cell tourism
Ethics of
publications
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Regulation of by the
Ministry of Health, MalaysiaNational Committeefor
Ethics in Stem CellResearch and Therapy(2009)
Health Technology
Assessment(HTA)division
National Pharmaceutical
Control Bureau(NPCB)
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Key points: Source of SCs
Allowed
Research on adultstem cells &embryonic SC
lines Use of surplus
embryos
Prohibited
Creation ofembryos forresearch
Xeno-transplantation
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Key points: Labs and facilities
Labs
Research labrequire GLP
Labs producing
cells for trialsmust be GMPcompliant
SC Clinics
Regulated underthe PrivateHealthcare
Facilities andServices Act(1998)
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Key points: Indications for therapy
Developmental and
experimental therapies Hsc for tissue repair, regeneration andvascularisation
Use of MSCs for various indications Use of neural stem cells, liver stem cells, etc.
Use of human ESCs
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2. Stem cells for
unproven indications
Indications
Stroke
Alzheimers
Parkinson
Kidney failure
Cerebral palsy
Down syndrome Many others
Challenges
Clinical trials are on-going but many areunder-powered
Issues of cell dose, routeof administration, use ofcontrols, etc.
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Cell therapy trials for strokeauthor details outcome
Kondziolka etal; 2000
12 patients with basal gangliainfarct transplanted withneuronal cells
Some improvements in the Europeanstroke scale but not significant
Kondziolka etal; 2005
RCT for stroke patients (7 pergroup)
ESS had no improvement but somesecondary outcome measures such as
Stroke Impact Scale, showedimprovement
Bang et al;2005
Autologous MSCs given IV 5-9 wks after onset; 5 patients;
No significant improvement
Yang et al;2006
Intrathecal injection of ESCderived NSC; 26 patients andno control arm
No adverse effects. Improvement inESS in 23 patients.
Lee et al; 2010 Autologous MSCs given IVafter onset of ischaemicstroke; 52 patients;
Safe and effective . But many questionson the design and results
Keith Muir,2013
Stem cells injected directlyinto damaged brain tissues
Claims that 5 patients are showingimprovement
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Japan: Regulation of stem cell
therapy is non-existent
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Can we trust the treatment being
marketed and provided Early trials showpromisefor some diseases
Unregulatedstem cell therapies have arrived
No conclusive evidence on safety andeffectiveness
Generally safe BUT there are reportedcomplications and failures
Need for clinical trials (for stem cell therapies) beregistered and regulated
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3. Mechanism of action:
Differentiation or paracrine?
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Paracrine effects: An overused
word but does not explain MoA
THE CLAIM: MSCs act via their trophic, immunemodulating, anti-inflammatory effects
Vaguestatement Putative mechanisms are so generic -
meaningless
These claimed mechanisms do not warrant
translation to the clinic at this time and stageAny putative paracrine factorinvolved
should be identifiedand then further
developed
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Mechanism of action: Definition
Specific biochemical interactionthroughwhich a drug produces its pharmacological effect
Specific molecular targetsto which the drugbinds, such as an enzyme or receptor
E.g. MoA of aspirin involves irreversible inhibition ofthe enzyme cyclooxygenase, therefore suppressing theproduction of prostaglandins and thromboxanes,thereby reducing pain and inflammation
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NSCs in an Alzheimers disease model:
Identifying key genes and proteins
Jamal et al, submitted 2014
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4. Stem cell tourism Clinics in China, Costa Rica,
Ukraine, Thailand, Mexicoand Russian and perhapsMalaysia too!
Cell harvested, processed,cultured from patients intheir countries andtransported
Cost: USD7500 for 100millions cells(USD5000 foreach additional 100 millions
cells
Stem cells isnow the
magic word
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Testimonies from
patients treated in China
Type 2 spinal muscular atrophy:Patient now able to open his fist and stretch each finger
Optic nerve hypoplasia:Improved vision
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The truth of the matter:
Deaths can occur
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Be cautious when assessing
claims of SC therapies
Claims based on
patientstestimonial
Multiple
diseases treatedwith same cells
No clear
documentationof source of cells
Claims thatthere is no risk
High cost Exactmechanism ofaction unknown
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5. The ethics of publications and
good research practice
Paper in Nature 2014 describing conversionof cells into embryonic stem cells by dippinginto acid bath was withdrawn
The disgraced scientist (Hwang):Paper in Science withdrawn (2006)
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Should it be driven
by science or profit?
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Summary: Will stem cells change
the transplantation horizon? The horizon has already beginning to change
More pre-clinical and clinical trials using MSCs and iPCS data looks promising but more work needs to be done
More companies investing money in cell therapies Key pre-requisites
Proven safety and efficacy high stringency
Accredited laboratories
Regulated Funding for research and development
Reimbursement for therapy
Treatment must be based on solid science and trials
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Thank you