stem cells canadian perspective - critical care …...stem cells –canadian perspective john laffey...
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Stem Cells – Canadian Perspective
John LaffeyCritical Illness and Injury Research Centre, Keenan
Research Centre, St Michael’s Hospital.
Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care Medicine,
University of Toronto.
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Conflict of Interest
• Tissue Regeneration Therapeutics, Toronto, Canada
• Orbsen Therapeutics Ltd, Galway, Ireland
• CommenceBio, California, USA
• Council member, Ontario Institute of Regenerative
Medicine
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Stem Cells – A Canadian discovery
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Griffiths M et al. Lancet 2005;366:245
Differentiation
Proliferation
Stem cell
Mature
cells
What are STEM CELLS?
Resident Lung Stem Cells
Embryonic Stem Cells
Induced Pluripotent Stem Cells
Endothelial Progenitor Cells
Mesenchymal Stromal Cells
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www.stemcells.nih.gov/info/
Bone Marrow Stem/Stromal Cells
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Advantages of MSCs
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Stem Cell Therapies –
focusing on lung Repair?
?
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Anaesthetize
Intubate
IV MSC
TherapyAnaesthetize
High Stretch
Ventilation
Assessment of
Recovery from
ARDS
48hrs
Compliance
ed 50%
Recover and
extubate
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MSCs enhance injury resolution
following VILI
Curley et al, Thorax 2012
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Hayes, Masterson et al, Anesthesiology 2014
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Gupta, Krasnodembskaya et al, Thorax 2012
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Time (Hours)0 12 24 36 48
Su
rviv
al
0.0
0.2
0.6
0.7
0.8
0.9
1.0
hMSCs (10-20 million/kg)
Vehicle/Fibroblast
Devaney et al, Thorax 2015
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Devaney et al, Thorax 2015
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• Ease of accessibility
• Absence of risk for the
donor
• Absence of pain for
donor
• Consistency in terms of
age at collection
Umbilical cord MSCs
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Sham E.Coli + Vehicle E.Coli + UC-MSC
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How do MSCs work?
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Curley et al, Anesthesiology 2013
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Krasnodembskaya et al, Stem Cells 2010
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Devaney et al, Thorax 2015
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MSCs enhance Macrophage Phagocytosis of
Bacteria
UNTREATED MSC TREATEDBACTERIA INFECTION
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Laffey & Matthay AJRCCM 2017
MSCs – Key mechanisms of Action
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hMSCs for ARDS…where
are we now?
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©2015 by American Society of Hematology
Blood 2015;126:2220
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• Understanding mechanisms of action
• Scaling MSC production for Clinical Trials
• Cryopreservation versus Fresh Cells
• Batch to batch variability
• Potency assays
• Optimal cell source
• Cost of large scale Clinical Trials for cell therapies
• Need for flexible approaches
• Turning critical care doctors into transplant physicians…
Stem Cells for ARDS – Challenges
Laffey and Matthay, AJRCCM 2017
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• Canadian…..contributions to health research and medicine. Two stand out as landmarks: the discovery of insulin in the 1920s and the discovery of stem cells in the 1960s.
• Canada founded the entire field of stem-cell science…….discovering neural stem cells, skin stem cells and cancer stem cells.
• Canada does this for a dime….The “all in” investment in stem-cell research in Canada …..is about $75-million [2012 Figures].
• Funding still seriously lags behind California, which, with roughly the same population as Canada, has committed $3-billion over 10 years for stem-cell research.
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Cell therapy trials in Ontario 2015-16
Brain and/or nerves Phase II using MSCs for Multiple
Sclerosis: Toronto*
Phase III using diabetes drug to
stimulate brain repair for malignant
brain tumours: Toronto*
Digestive systemPhase III using MSCs to induce
remission of Crohn’s disease:
London and Toronto
HeartPhase II using genetically modified
stem cells following heart attack:
Ottawa and Toronto*
Phase II using MSCs for advanced
heart failure with left ventricular
assist device: Toronto*
SpinePhase I/II using neural stem
cells for spinal cord trauma:
Toronto*
BloodPhase I using immune cells for
blood cancer relapse after
bone marrow transplantation:
Toronto*
JointsPhase I-II using stem cells mid-
to late-stage knee osteoarthritis;
Toronto*
2015-16
9 trials
11 partners
3 Ontario
cities
655+ patients
Billions of
stem cells
* OIRM researchers leading trial
Critical carePhase I using MSCs for septic
shock: Ottawa*
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Hematopoietic stem cell transplantation
First Animal
studies
1954
First Human
studies
1957
First Proof
of efficacy
(in AML)
1977 1982/6
Proof of
efficacy
in CML
Ongoing Discoveries
e.g. MSCs for GVHD
2001-16
Human Allogenic
BM Transplant
1971
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• Stem cells offer considerable potential for Critical Illnesses
– Pre-clinical studies highly encouraging
– MSCs now in early phase Clinical Studies for ARDS
• Clinical Translational pathway likely to be lengthy and there
will be setbacks...
• Twin-track strategy of pre-clinical research and early phase
clinical translational studies in progress
• Canada’s role in realizing clinical potential of stem cells
– World leading Preclinical/Discovery science
– CISS-1 Study a major step forward in Sepsis
Stem Cells – A Canadian Perspective
Laffey and Matthay, AJRCCM 2017
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Acknowledgements
Gerard Curley
Mirjana Jerkic
Stephane Gagnon
Claire Masterson
Allen Volchuk
Grace Hogan
Lindsey Ormsher
Linda Garces
Haibo Zhang
Wolfgang Kuebler
Sergio Grinstein
Timothy O’Brien