Prof. Datuk Dr a Rahman_ Stem Cells_The Current State of Its Science and Ethics

8/10/2019 Prof. Datuk Dr a Rahman_ Stem Cells_The Current State of Its Science and Ethics

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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

Documents

Prof. Datuk Dr a Rahman_ Stem Cells_The Current State of Its Science and Ethics