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Professor Richard Boyd
Group LeaderStem Cells and Immune Regeneration Laboratory,
Dept Anatomy and Developmental Biology
ImmunoGlobalGroup Hong Kong Stem Cell bank
and clinic
MAGELLAN STEM CELLS
“ Stem Cell Medicine” From Placenta to adults – where are we now?Future therapies needs research, commercial partners, Govt
support and public involvement!
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Acknowledgements
AsthmaTracy Heng
Sacha KhongTolerance
Tracy HengJess Morison
FRCAnne Fletcher
Peking Union Medical School“Robert” Zhao
Genesis Stem Cells Pty LtdJiansheng (Jason) Meng
Jianqiang YinYang (Claire) Zeng
Thymus regrowth and stem cellsNat Seach, Kahlia Wong, Chew-Li Soh, Ed Stanley, Marco Barsanti, Maree Hammett, Lisa Spyroglou, Jarrod Dudakov,
Gabby Goldberg, Jayne Sutherland (Jade Homan, Jade Barbuto)Neonatal stem cells
Immune RegenerationMSC & AEC in Wound Repair
Standard Operating Procedures for isolation of AECsAdrienne Calder, Anthony Park, Abdulaziz Alsharif
Associate Prof ANN CHIDGEYProfessor ALAN TROUNSON,
Zhicheng XiaoMark “every lab should have one” Malin
Louis Chan, Robert Chin, Anthony Wong, Kenneth Chan
AVSC – Magellan – CMA Dr Dan Bates, David Connell Peter Hansen, Peter Britton, Geoff Barnard
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Why the need for stem cells?
• Children develop debilitating diseases that effect them for life
• AND• The older we get, the sicker we get !• Average age has gone from ~30 in 1800’s to now over 80• Living longer but often carrying disease or degenerative
conditions– Quality of life is suffering….
• MAJOR UN-MET CLINICAL NEEDS IN REGENERATIVE MEDICINE
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HURDLES – but patients impatient!
• Ethical• Strict Government regulations now in place
• Safety• Must have pre-clinical animal data
• Practical• Which ones to use?• Commercial IP – who owns it?
•Clinical translation• Need care, safety, rigour…. not everything works..
• Funding - public and private co-investment!
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Our Goals
To establish:• “State of the Art” (Alpha-type) stem cell treatment
clinics in Australia• prestigious international partners, eg CIRM• rigorous pre-clinical studies “Evidence based medicine”• Isolating, analysing and banking a range of stem cells
– Newborn stem– Adult stem cells
• Innovative, cutting-edge clinical research laboratories
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Monash University
Stem Cells Meet Immunology - a new research, therapeutic and commercial platform
Department of Anatomy and Developmental Biology#1 Ranking in Australia
Extensive Research and Development Pipeline in Stem Cells and Immunology
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I$ it worth it?
Returns to UK publicly funded cancer-related – (Glover etal BMC Med 2014)
• Total expenditure 1970/2009 - £15 billion• Net monetary benefit of prioritized interventions due to this
research was £124 billion• Internal rate of return for an elapsed time of 15 years – 10%• Compared with previous estimate of 9% for cardiovascular
research
Saving lives and better $ returns than bank interest
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Economic Impact of theHuman Genome Project
“How a $3.8 billion investment drove $796 billion in economic impact, created 310,000 jobs and launched the genomic revolution”
Prepared by Battelle Technology Partnership PracticeMay 2011
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Stem cells……
• Why are they important?• What can we do with them?
Alan Trounson
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Which stem cells to choose..??
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Many Types of Stem Cells!
Pluripotent
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Induced pluripotential stem cells (iPS)Turning adult mature cells into your own “ES cells”
Adult somatic cells(normal or disease)
“ES” genes(proteins)Oct4, Sox1,2,cMycNanogLin28
Reprogramming
ES cells
Self repair kit; new therapies, diagnostics, disease modeling
ISSUES?? Safety, cancer, autoimmunity, really self??
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iPS can be used to create disease in a test tube – diagnosis/drug testing
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Are we missing something??
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Miracles in motion…
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Perinatal Stem Cells
• A source of multipotential/pluripotential stem cells, that are safe, ethical and effective in treating a wide range of diseases
• A 3D membrane suitable for stem cell support and tissue regeneration, treating wounds, ulcers and burns?
• Cord blood, cord tissue, amnion, amnion fluid
Nature’s body repair kit?
…there is a caveat….
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Sources of stem cells in new born…
• Umbilical Cord Blood– Haemopoietic stem cells (HSC)– A research, clinical and
commercial gold mine?
www.healthystarttolife.monash.org/
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Cord blood
• For transplant: need ~ 25x106 TNC / kg
= 1.25 billion for 50kg patient• Hence need > two cord bags for transplants
– one engrafts but often the other dominates• (MSC can aid engraftment: HSC proliferation
but also improving BM “niche”?)• Is there another source?
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Comparison of stem cells derived from Placenta and Cord blood
• Average weight of a placenta = 500g• Average weight of a cord blood unit = 40g (converted from volume).
Whole placenta One Cord blood unit
TNC 2.30 x 10^9 2.12 x10^8
HSC 3.55x 10^7 1.20 x 10^6
MSC 2.60 x 10^8 Not detected
whole placenta one cord blood unit0
500000000
1000000000
1500000000
2000000000
2500000000
TNCs of placenta is 11 times of CB
whole placenta one cord blood unit0
10000000
20000000
30000000
40000000
HSCs of placenta is 30 times of CB
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Cord blood (HSC) trials
• 919 registered trials (NIH Clin Trials.gov)• Most haemopoiesis recovery in cancers; very promising • Non cancers:
– BM failure (including MDS)– Inborn errors of metabolism (enzyme storage disease)– birth/prematurity conditions: cerebral palsy; anemia;
intracranial hemorrhages; retinopathy respiratory distress syndrome; Bronchopulmonary Dysplasia
– TBI, stroke, autoimmunity
Joanne Kurtzberg (Duke Uni)
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Amnion Stem Cells
Readily availablePlentiful supplyNo ethical issues
Towards a cure
Sean Murphy
Made by the baby for the baby.
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Chorion Mesenchymal Stem Cells
Amnion membrane Mesenchymal Stem Cells Amnion Epithelial Cells
Placenta: Placenta derived stem cells
Umbilical CordHematopoietic Stem Cells Mesenchymal Stem Cells
Placental tissue Stem CellsAnn Chidgey
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ZYGOTE
BLASTOCYST
Hypoblast Epiblast
Mesoderm
WEEK 1
WEEK 2
WEEK 3
Amnion Epithelial Cells
Endoderm Ectoderm
Embryonic Stem Cells
AEC formed from the Epiblast - multipotent stem cells
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freshly isolated hAECs
100m
Siva Ilancheran, Ursula Manuelpillai, Sean Murphy, Euan Wallace, Graham Jenkin
muscle
lung brain liver
heart
pancreas
fat
bone
Amnion Epithelial Cell Differentiation
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AEC express markers associated with stem cells
• Express markers associated with stem cells
• Risk of tumor formation low compared to ESC/iPS
EpCAM 94%Ck7/8 99%SSEA 3 9%SSEA 4 44%
TRA 1-60 10%TRA 1-81 10%Oct-3/4 5-15% Nanog 5-15% Sox-2 5-15% CD117 20% low CD34 <1%
CD90/105 <1%
Miki et al. 2005, Ilancheran et al. 2007, Murphy et al. 2010
BM MSC ESC hAEC P0 hAEC P5 H Control L Control02468
101214161820
Telo
mer
e Le
ngth
(k
bp)
• Relatively long telomere length
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Why Amnion?
• Anti- inflammatory• Immune suppressive• cells secrete appropriate cytokines• Multipotential for differentiation• Antimicrobial • Reduces pain• Reduces scarring• 3D ECM –complex, multilayered• Leads to…..pre-clinical to clinical applications
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History of Amniotic Membrane TransplantIn 1910, Davis was the first to introduce the use of
human amniotic membranes (AMs) as a skin graft. In 1913, Sabella used AMs as a permanent coverage
over wounds in burns patients.In 1952, Douglas was the first to report the use of AMs
as a temporary biological dressing in the coverage of burns.
In 1995 Kim and Tseng reintroduced the idea of amniotic membrane for ophthalmic use which has since become increasing more popular.
International Journal of Dermatology 2009, 48, 935-940
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Amniotic membrane transplantation for burns and wound healing
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Amnion trials
• In addition to burns…..• >160 trials amnion membrane +-/- stem
cells– Corneal - Limbal stem cell insufficiency; data
incomplete– New trial lumbar fusion for degenerative discs;
Jan 2014– Abdominal and skin surgery– Under utilised!
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Something to think about…..
The mother is living with a transplant!
Why no rejection?
What actually happens with pregnancy and birth…?
What therapeutic tricks can we learn??
Pregnancy - birth – development
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Umbilical cord is MUCH MORE than HSC immune suppression
• Tregulatory lymphocytes (Tregs) • CD4+, CD25+, FoxP3+; release immune suppressing factors
• Mesenchymal Stem Cells• Potent inhibition of immune function; anti-inflammatory
• Combination:• may prevent maternal – fetal rejection;• help “self tolerance” induction?
• MAPC (multipotential “adult” progenitor cells; very low number and variable)
• Cord Blood “ cells” can cross the blood brain barrier
(function of cells or age of recipient?)Joanne Kurtzberg
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• 96 trials (May 4th 2014); very few results posted~!• Supplement to HSCT – preventing GvH and
promoting engraftment (HSC expansion/ recovery of niche?) (AuxoCell; Mesoblast)
• HIV – can MSC block immune activation cell death?• Organ transplants (blocking rejection)
• Diabetes (I and II), • Autoimmunity: MS, RA, SLE, • Osteoarthritis
Cord tissue MSC Trialsmaking use of anti-inflammatory/ immune suppressive;
repair induction
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What about MSC/ Amnion for asthma?
Key commercial partnership with Mesoblast ARC linkage grant
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www.monash.edu.au
35
Lung disease optimal for MSC treatmentTracy Heng
(D. Prockop 2009 Mol Ther)
95% cleared from blood < 5 mins
Half-life = 24hr in lungs
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www.monash.edu.au
36
Ovalbumin-induced asthma modelTracy Heng
0
OVA/alum
8 9 10
IntranasalOVA
12
Analysis
11
DAYS
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www.monash.edu.au
37
OVA-sensitised mice develop cellular infiltration of the airways
FSC MHC II
CC
R3
CD
3/B
220
CD
11c
SS
C
Mo
Gr
Ly
DCMac
BT
Neu
Eo
OVA SENSITISED
PBS UNSENSITISED
(T.Heng)
*
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www.monash.edu.au
38
… MSC reduce eosinophils in asthma lungs
(T.Heng et al 2014)
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Multiple Sclerosis: Towards a cure
MSC and AMNION-DERIVED STEM CELLS SUPPRESS THE MULTIPLE SCLEROSIS-LIKE DISEASE IN MICE
McDonald, Jenkin, Bernard
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Veterinary applications of MSC’s(Cord and Adipose)
To improve animal health; pre-clinical models for humans• Tendons, ligament injuries, and fractures, • Osteoarthritis • Cancer• Diabetes• Kidney and heart disease• More than 5,000 horses treated since 2003• More than 4,500 dogs treated since 2006• More than 500 dogs, cats, horses in Australia
Commercial partners
Australian Veterinary Stem Cells ,
Vet Stem, San Diego
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Veterinary applications - osteoarthritis
Expanded MSC• No serious adverse effects• Strong evidence of pain reduction and return
of capacity • >85% of all animals responded• 100% of younger dogs
(Australian Veterinary Stem Cells , Vet Stem)
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To the Clinic - a practical solution?
• Very expensive – who pays?
• In Australia clinical treatments can be conducted under the TGA “Biological Exemption”
• Basically states “ Clinician takes full responsibility for what the patient receives, for one clinical treatment (can be multiple procedures but only for one treatment)”
• Companies and patients can pay for therapy development
• But……
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Stem cell therapies: Our code of ethics
We have formed the “Australian Autologous Cell Therapies Group”
Developed a Code of Ethics– Academic, clinical and commercial “clinical groups”– make certain maximal patient safety; clinical rigour, – evidence based treatments, – appropriate thorough patient follow-up; – on-line data management (we are working with
“Clinical Intelligence Pty Ltd. Melb)– Peer group evaluation of data;– International presentations and publications– Appropriate inclusion of commercial partners
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Human Chondral Defects, OA Dr DAN BATES
• 12% of the population will suffer chondral lesions
• These progress to osteoarthritis
• >5% of the Australian population suffer Osteoarthritis (3.7 million)
• Costs 23 billion dollars per year to Australian economy
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Human Evidence – MSC Safety
Author Patients Disease Injection Follow-up Study Symptom Improvement
Wakitani 2010
41Knee
OsteoarthritisIA 11 years
Safety Study
No Cancer, No infections
Centeno 2010/2011
339Knee, Back,
HipsIA,
Paraspinal2 years
Safety study
No Cancer, No infections
Rodrigeuz 2012
13Rheumatoid
ArthritisIV and IA
13 months
Safety study
One episode of fever & myalgia
Guadalajada 2012
50Perianal fistulas
Local 3 yearsSafety
and efficacy
No Cancer No injection
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Left Lateral Femoral Condyle – Pre-treatment
Chondral Defect
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12 Months post treatment
Defect Coverage at 12 months (Grey Line)
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Osteoarthritis Knee– WOMAC*
pre-treatment 1 month 3months 6months 12 months0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
IH Left PFJ**IH Right PFJ**GH Grade 4TF Grade 3**
WOMAC24 Questions on pain, disability, joint stiffness
Grade 4 OA • Need multiple
injections• Combination cell
therapy
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Osteoarthritis Clinical TrialsDrs Julien Freitag / Dan Bates
• Melbourne Stem Cell Centre – Clinic, Box Hill
• “Clean Room” (moving to GMP)– Magellan
• Two Randomised Clinical Trials• Monash/ Latrobe University Ethics• Strong research program
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How to maximise MSC effects in OA
• Need to reduce pain• Restore cartilage• Improve strength• But do MSC’s perform this or mediate
through endogenous cells• MSC Short lived!
Need to incorporate support matrices….to improve MSC function and localise to injury site
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Tissue Engineering using nanobiotechnology
1. Engineer scaffolds that promote stem cell repair2. Fabricate “smart” scaffolds that can instruct stem cells.
David NisbetJohn ForsytheNick BoydMonash Engineering
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Tissue Engineering Scaffolds
Important Features
• Interfiber distance• Surface functionality
Nisbet DR, Forsythe JS, et al. J. Biomater. App. 2009
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Factors Controlling Nerve Growth
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Interaction of Stem Cells with Nanofibrous Scaffolds
Nisbet DR, Forsythe JS, et al. J. Bio. Sci. Poly. Ed. 2008
Unmodified nanofibrous scaffold
200μm
A
PCL nanofibrous scaffold surface modified
B
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3D electrospun/electrosprayed nanocompositessmart surfaces for stem cell therapies Nick Boyd
Nano-HAp suspension
+kV
Collector
PCL + GAA/Pyr+kV
Collector
Step 1: Electrospin PCL Step 2: electrospray nano-HAp
• Use electrospray duration to control surface coverage density of nano-Hap• Then add layer-by-layer growth factors
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A
100nm
C
100nm
E
100nm
B
1μm
D
1μm
F
1μm
3D PCL + nano-HAp (low)
3D PCL + nano-HAp (high)
3D PCL
✓
3D electrospun/electrosprayed nanocomposites
Electrospun PCL with varying levels of nano-HAp coating surface density, controlled by duration of electrospraying time. All fibres were electrospun from 15wt% in GAA/pyr(2%), at +12.5kV, -10kV, flow rate: 2.0ml/hour, WD: 13cm, RH: 10-20%. (A, B) no HAp electrosprayed onto the fibres. HAp electrospray from multi-nozzle head using multi-jet spray onto a rotating drum collector. 0.1% (w/v) in methanol, WD: 20cm, R.R: 20mls/hour, +28kV, -20kV was applied to (C,D) for 24 minutes, and (E,F) for 48 minutes.
B
C
D
E
F
100nm 100nm
1μm
C E
F
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Stem cell NEW HORIZONS!
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Breast milk – natures “jewel” for health
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The Value of Maternal Stem Cells at birth
Placental, chorion, decidual tissue• Maternal Mesenchymal Stem Cells for maternal use• Females have higher incidence of autoimmune disease
Breast milk!• Contains ~1 million cells/ml• Immunity- Type II macrophages, T regulatory cells
-> key elements in preventing maternal-fetal rejection also Ab and T cell based immunity
Stem Cells - breast duct -derived pluripotential “epithelial” stem cells; Mesenchymal Stem Cells
• Present as long as lactating; increased with feeding
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These “newborn” stem cells are so valuable!- should be banked
• Nature’s whole body repair kit• ProStemCell Pty Ltd Hong Kong• Comprehensive stem cell bank
• Cord blood• Cord tissue (isolated MSC)• Amnion:
• single cells; • cell intact membrane • Acellular intact ECM
• Cord serum/plasma• Breast milk
Hong Kong Stem Cell Bank and clinic
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Summary – Perinatal Stem cellsCORD Blood/Tissue• HSC – haemopoiesis• MSC /Tregs – autoimmune disease• “MAPC” tissue repair – cross blood brain barrierPLACENTA• Abundant HSCs, MSCs, AMNION• AECs (100-200 x106 cells per sample• Readily available• Immunosuppressive/ anti-inflammatory• AEC /MSC strong evidence of lung, liver repair-> Can we create Thymus epithelial stem cells??
AMNION MEMBRANE ENHANCES WOUNDS AND BURN REPAIR • Acellular membrane (ECM) for “off the shelf” cell support and tissue
engineering
• Amazing scope for Regenerative Medicine
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New Born Stem Cell Banking – a logical choice
Bank it
Donate it
BUT don’t discard it.
It just makes sense!
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The BIGGEST PRACTICAL PROBLEM….
How can we overcome this??
• Unless they are your own, stem cell therapies will be considered as foreign transplants and
• will be rejected by the patients immune system!
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The thymus
• creates all T cells• deletes or silences autoreactive T cells = self tolerance
Thymus key to long term tolerance of donor therapeutic transplants
Most diseases needing therapy are in the aged…
BUT the thymus degenerates with age?!
Can we use stem cells to restore the old thymus for tolerance inducton?and overcome age-immunodeficiency!
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Can we create thymic stem cells?
Derivation of thymus from ES cells:
- GFP targeted “Fox N1” (mouse, human)
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Differentiation of FOXN1GFP/w hESCs into hTECS
(Ng et al, 2008, Nature Protocols)
BFGFP
FACS analysis, qPCRs
Chew-Li Soh et al 2014
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Inducing tolerance to stem cell therapeutics
Chidgey et al Nature 2008
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What are the three worst words a patient can hear?
YOU HAVE CANCER
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612 × 358 - en.wikipedia.org
Immunotherapy
Stem cells to boost the immune system to kill cancer
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• Combines the power of Ab specificity and flexibility with the killing efficiency of T cells
• Cancer recognition through Ab engineered into T cell membrane
• linked to signal transduction molecules – binding triggers activation
• T cell directly kills cancer cell
Chimeric Antigen Receptor (CAR)
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•CAR- T cell Therapy
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Stem cell technology enhances immunotherapy!
• CAR- technology can arm millions of patient T cells against their cancer
• Eventually these cells will be “worn out” and severely depleted
• Induced pluripotential stem cell (iPSC) technology can overcome this
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Stem cell technology enhances immunotherapy!
• Create iPSC from CAR-T , • effectively immortal, • limitless self renewal, • re-create T cells from these iPSC,• T cells retain the cancer specificity• Can be infused into the patient• OR• Cryopreserved for future relapse
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Table 2. Summary of clinical outcomes.Characteristics No. of patients (N = 16) Overall complete response to salvage chemotherapy* 7 44%
Overall complete response to 19-28z CAR T cells 88%In patients with morphologic residual leukemia (n = 9) 7 78%Complete remission (CR) 10 63%Complete remission with incomplete count recovery (CRi) 4 25%Molecular complete remission (CRm)‡ 12† 75%Median time to CR/CRi (days) 24.5Post-CAR T allo-SCT (n = 10 eligible patients)§ 7 70%
“Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia” Davila etal Sci Transl Med 2014
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SUMMARY• The world of stem cell therapies is all but on us
– Melbourne Stem Cell Clinic open for business• “Hard yards” of research now gaining clinical traction• The transition from promise to reality is delicately
poised• Funding the key !
– are there commercial partners?– How much should the government pay– Health insurance companies….??– Can/should patients pay for their evolving
therapies?
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“Proposition 71 authorizes essential research for new cures intended to save millions of lives” $US3Billion
04/08/2023
Californian Institute for Regenerative Medicine
Alan Trounson
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CIRM - Driving Partnerships in Translation and Preclinical Research
Inno
vatio
n an
d so
lutio
ns • Academia• Research
infrastructure• Research
capacity• Innovation• IP
Regu
lato
ry e
xper
ienc
e an
d fo
cus • Industry• Manufacturing• Standards• Focus –
milestones, go-no-go decisions
• Relevance – competition
• IP utilization Del
iver
y of
cel
l the
rapi
es • Clinical
Medicine• Patients• Clinical
infrastructure• Counseling• Monitoring
long term• Clinical trial
capacity
Globalize the Initiatives Alan Trounson
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Therapy Progress: Neurological Disorders$94 million
04/08/2023 83
Epilepsy $1.7 million (1)3 million in US
Spinal muscular atrophy $5.6 million (1)
Stroke $20 million (1)140,000 die/year
“There are so many things doctors can do with stem cells that will really help.”- K. Michael Cooper (stroke)
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Therapy Progress: Neurological Disorders$94 million
04/08/2023 84
Autism $1.5 million (1)
1 in 110 kids in US
Huntington’s disease$6.6 million (2)30,000 in US
Spinal cord injury$26.5 million (2)200,000 in US
“Turning stem cells into cures”- Roman Reed
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Therapy Progress: Neurological Disorders $94 million
04/08/2023 85
Lou Gehrig’s disease(ALS) $10.8 million (1)5,600 diagnosed/year
Alzheimer’s disease$3.6 million (1)
5 Million in the U.S.
Parkinson’s disease$13.9 million (3)
50,000 diagnosed/year
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Phase I/II Spinal Cord Injury Trial
• Multi-segmental gains
• ASIA LT changes correlate with quantitative thresholds
• University of Zurich - Balgrist
Hospital, Swissmedic authorised
• Now authorised in Canada and US
• 12 chronic stage patients; T2-T11
injury – enrolling A, B, C