Stem Cells Canadian Perspective

Stem Cells Canadian Perspective John Laffey Critical 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.

Conflict of Interest Tissue Regeneration Therapeutics, Toronto, Canada Orbsen Therapeutics Ltd, Galway, Ireland CommenceBio, California, USA Council member, Ontario Institute of Regenerative Medicine

Stem Cells A Canadian discovery

What are STEM CELLS? Resident Lung Stem Cells Embryonic Stem Cells Induced Pluripotent Stem Cells Endothelial Progenitor Cells Mesenchymal Stromal Cells Mature cells Stem cell Proliferation Differentiation Griffiths M et al. Lancet 2005;366:245

Bone Marrow Stem/Stromal Cells www.stemcells.nih.gov/info/

Advantages of MSCs

Stem Cell Therapies focusing on lung Repair??

Anaesthetize Intubate IV MSC Therapy Anaesthetize 48hrs Compliance ed 50% Assessment of Recovery from ARDS High Stretch Ventilation Recover and extubate

Curley et al, Thorax 2012 MSCs enhance injury resolution following VILI

Hayes, Masterson et al, Anesthesiology 2014

Gupta, Krasnodembskaya et al, Thorax 2012

1.0 0.9 Survival 0.8 0.7 0.6 0.2 0.0 hmscs (10-20 million/kg) Vehicle/Fibroblast 0 12 24 36 48 Time (Hours) Devaney et al, Thorax 2015

Devaney et al, Thorax 2015

Umbilical cord MSCs Ease of accessibility Absence of risk for the donor Absence of pain for donor Consistency in terms of age at collection

Sham E.Coli + Vehicle E.Coli + UC-MSC

How do MSCs work?

Curley et al, Anesthesiology 2013

Krasnodembskaya et al, Stem Cells 2010

Devaney et al, Thorax 2015

MSCs enhance Macrophage Phagocytosis of Bacteria BACTERIA INFECTION UNTREATED MSC TREATED

MSCs Key mechanisms of Action Laffey & Matthay AJRCCM 2017

hmscs for ARDS where are we now?

2015 by American Society of Hematology Blood 2015;126:2220

Stem Cells for ARDS Challenges 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 Laffey and Matthay, AJRCCM 2017

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.

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* 2015-16 9 trials 11 partners Heart Phase 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* Blood Phase I using immune cells for blood cancer relapse after bone marrow transplantation: Toronto* Joints Phase I-II using stem cells midto late-stage knee osteoarthritis; Toronto* 3 Ontario cities 655+ patients Billions of stem cells Spine Phase I/II using neural stem cells for spinal cord trauma: Toronto* Critical care Phase I using MSCs for septic shock: Ottawa* Digestive system Phase III using MSCs to induce remission of Crohn s disease: London and Toronto * OIRM researchers leading trial

Hematopoietic stem cell transplantation First Proof of efficacy (in AML) Ongoing Discoveries e.g. MSCs for GVHD 1954 1957 1971 1977 1982/6 2001-16 First Animal studies First Human studies Human Allogenic BM Transplant Proof of efficacy in CML

Stem Cells A Canadian Perspective 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 Laffey and Matthay, AJRCCM 2017

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