Funded Disease Team Projects
OIRM’s research program includes large, disease-based team grants, smaller New Ideas Grants to answer basic research questions and Post-doctoral Fellowships.
2018-2019 Disease Team Awardees:
Towards a Cell Therapy Application Using Pluripotent Stem Cell-Derived Heart Muscle Cells to Regenerate Injured Hearts
Michael Laflamme, University Health Network ($370,000)
Graham Wright, University of Toronto
Gordon Keller, University Health Network
Ren-Ke Li, University Health Network
Terrence Yau, University Health Network
After myocardial infarction, “heart attack”, the heart muscle lost is replaced by non-contractile scar tissue, often initiating progressive heart failure. Our current options for treating post-infarct heart failure are limited, and it remains a disease with high morbidity, mortality and societal costs. The ability to “remuscularize” the infarct zone by transplanting cardiomyocytes, heart muscle cells, derived from human embryonic stem cells (hESCs) represents a potentially revolutionary new therapy for patients suffering from this disease. In order to treat the injured region a large number of cells are required. To address this, our team has translated protocols for the cardiac differentiation of hESCs from the lab bench to large-scale production, and we are now able to routinely generate hESC-derived cardiomyocytes in large cell batches. We have also developed improved protocols that guide the differentiation of hESCs into specialized cardiac subtypes, including the ventricular cardiomyocytes that are needed for infarct repair. This project will now perform proof-of-concept work to determine if the transplantation of hESC-derived ventricular myocytes can remuscularize the infarct scar and improve contractile function in a well-validated pig model of post-infarct heart failure. These studies will test the safety and efficacy of this novel cell therapy using endpoints including tissue structure, contractile function, as well as ECG recording and electrical function.
Cellular Immunotherapy for Septic Shock (CISS): Research to Move Stem Cells Through the Clinical Pipeline
Lauralyn McIntyre, Ottawa Hospital Research Institute ($370,000)
Shirley Mei, Ottawa Hospital Research Institute
Kednapa Thavorn, Ottawa Hospital Research Institute
Claudia dos Santos, St. Michael’s Hospital
Jason Acker, Canadian Blood Services
Dean Fergusson, Ottawa Hospital Research Institute
Septic shock is a devastating illness and the most severe form of infection seen in the intensive care unit (ICU). Approximately 20 – 40% of patients will die and survivors suffer significant long-term impairment in function and reduced quality of life. Despite decades of research examining different therapies, none has proven successful and supportive care remains the mainstay of therapy. Mesenchymal stem cells (MSCs) represent a novel treatment, and have been shown to modulate the immune system, increase clearance of bacterial pathogens, restore organ function, and reduce death in preclinical models. Our research team was the first in the world to have conducted and completed a Phase I clinical trial that evaluated MSCs in patients with septic shock. Our trial established that MSCs appear safe and that a randomized controlled trial is feasible. Based on these results, we are now moving to a larger clinical trial at several academic hospitals across Ontario and Canada. This Phase II RCT (CISS2) will continue to evaluate safety, assess if there are strong signals for clinical benefit, and examine mechanisms and biological effects of MSCs. An economic analysis will also determine if the treatment is cost effective. This project will also focus on the optimization of a cryopreserved MSC product, identify bio-signatures tailored to septic shock to further identify potent cells, and to develop MSC modifications to further improve their performance characteristics for evaluation in future septic shock clinical trials.
Stem cell approaches to repairing damaged white matter in the brain of children and teenagers
Freda Miller, The Hospital for Sick Children ($370,000)
Donald Mabbott, The Hospital for Sick Children
Paul Frankland, The Hospital for Sick Children
David Kaplan, The Hospital for Sick Children
Cindi Morshead, University of Toronto
Douglas Munoz, Queen’s University
Jing Wang, Ottawa Hospital Research Institute
Ann Yeh, The Hospital for Sick Children
Damage to brain white matter occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. Our research project is focused on enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident precursor cells that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous precursors to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from neural precursors and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic. To do so, we will perform preclinical work with metformin in different mouse models of white matter damage, and will search for additional methods of enhancing oligodendrocyte formation, since combinatorial approaches for treating white matter damage will likely be the most efficacious. At the same time, we will pursue a pilot clinical trial of metformin for pediatric demyelinating disease using outcome measures we recently developed. Positive results in our clinical trial will lead to a dramatic shift in how we treat children/teenagers with white matter injury, and will pave the way for future additional clinical trials in children and adults with white matter damage.
Stimulating Muscle Repair for Duchenne Muscular Dystrophy
Michael Rudnicki, Ottawa Hospital Research Institute ($250,000)
Penney Gilbert, University of Toronto
Patrick Gunning, University of Toronto
William Stanford, Ottawa Hospital Research Institute
Jodi Chardon, The Ottawa Hospital
Hugh McMillian, Children’s Hospital of Eastern Ontario
Duchenne Muscular Dystrophy (DMD) is a devastating genetic disease that affects 1/3500 boys that is characterized by progressive muscle wasting and premature death in the second or third decade of life. No effective cure-based therapy exists for DMD.Our research goal is to implement innovative therapeutic approaches for treating DMD patients to extend physical mobility and enhance quality of life by stimulating skeletal muscle regeneration using small molecule drugs. We believe that therapies targeting muscle stem cells to stimulate muscle regeneration can be combined with therapies to restore dystrophin expression to more effectively treat DMD. In this project, we will conduct the preclinical research necessary to bring innovative therapies to human clinical trials. We have identified a panel of small molecule drugs that improve the regenerative defect in DMD muscle stem cells. We will first test drugs on satellite stem cells that have been isolated from normal and dystrophic mice to confirm the drug activity and to determine the optimal dose. We will then treat normal and dystrophic models with drugs to test the effects and whether the drug enhances repair. Long-term experiments will be performed where drugs are given to dystrophic mice over several months to test whether drug treatment alleviates the dystrophic degeneration of muscle. These experiments will identify which drugs work best for preventing degeneration of dystrophic muscles. These promising drugs will be tested on human muscle stem cells to confirm that the drugs act on human cells in the same way they act on mouse cells. These muscles will be treated with candidate drugs to test whether muscle repair is enhanced. We will employ medicinal chemistry to explore optimization of lead candidates. Several of the drugs we are testing are human experienced, which could accelerate the pathway to clinical trial.
Generation and clinical use of white blood T-cells from stem cells for immune-regeneration and immunotherapy
Juan Carlos Zúñiga-Pflücker, University of Toronto, and Sunnybrook Research Institute ($250,000)
Donna Wall, The Hospital for Sick Children
T-cells are a subset of white blood cells that play a central role in immunity against infectious diseases and cancer. Unlike all other blood cells, which develop within the bone marrow (BM), T-cell development is dependent on migration of BM-derived progenitors to the thymus. However, thymus function can be severely damaged during radiation/chemotherapy and also deteriorates with age. While BM transplant is a potentially curative treatment for leukemia and other blood disorders, delayed T-cell recovery increases the risk of opportunistic infections and cancer relapse leading to high mortality rates. While some treatments appear to provide some level of protection to the thymus from the damage by radiation/chemotherapy, no method to date has been successful in increasing the likelihood of effective T-cell reconstitution or repairing thymic function. The goal of this proposal is the clinical translation of in vitro technology for the differentiation of hematopoietic stem cells into progenitor T-cells (proT) using a fully-defined and animal-free method. Our team will establish a cGMP compliant protocol based on our technology to produce a proT-cell clinical product that will be used to initiate a first in-human clinical trial validating the safety and efficacy of these proT cells in humans. This will lead to a better understanding how proT-cell infusions following hematopoietic stem cell transplantation (HSCT) can improve T-cell recovery and patient outcomes.
INCuBATOR: New Cell Treatments for Lung Injury in Babies – Getting research faster and safer into patients.
Bernard Thebaud, Ottawa Hospital Research Institute ($100,000)
Dean Fergusson, Ottawa Hospital Research Institute
Justin Presseau, Ottawa Hospital Research Institute
Kednapa Thavorn, Ottawa Hospital Research Institute
Extreme prematurity is the main cause of mortality and morbidity in children before 5 years of age. The most severe complication is bronchopulmonary dysplasia (BPD), a chronic lung disease that damages the lungs of preterm babies requiring a breathing machine and additional oxygen to stay alive. Because these injuries occur in developing organs, consequences are life-long and carry a high economic burden. Our lab was the first to show that umbilical cord-derived mesenchymal stromal cells (UC-MSC) could protect the lung from injury in neonatal laboratory models. UC-MSC has many advantages, especially for babies as the cells are easy to obtain after birth without harming mother or baby. These cells also have a higher repair capability and expansion potential. Our team has developed a new protocol that yields high numbers of low passage, GMP manufactured clinical grade UC-MSCs. In addition, our INCuBATOR approach will speed up the process of bringing this promising cell therapy into patients. In preparation for a Phase I human clinical trial, our team will perform several studies to: 1) ascertain that the cell product is safe and efficient through rigorous laboratory studies and reviews of research of others using a systematic analysis; 2) interview parents of preterm infants, physicians and researchers to obtain their views on the conduct of stem cell trials in babies and 3) conduct an economic evaluation to ensure that MSC therapy for BPD is economically viable. This information will help in designing the best possible clinical trial in babies. Thus, the INCuBATOR project will accelerate a potential breakthrough therapy that will improve the outcome of extreme preterm babies in Canada and world-wide
Cell transplantation to preserve central vision
Valerie Wallace, Krembil Research Institute ($100,000)
Andras Nagy, Lunenfeld-Tanenbaum Research Institute
Carol Schuurmans, SunnyBrook Research Institute
Molly Shoichet, University of Toronto
Derek van der Kooy, University of Toronto
Late stage retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative diseases that rob patients of central high acuity vision. The multiple underlying factors of these diseases converge on the loss of light sensitive cone photoreceptors in the central macular region of the retina, resulting in central vision loss. Rod photoreceptors and RPE are essential for the survival and function of cone photoreceptors. Current efforts to deploy cell-based retina repair strategies are hampered by several barriers, including a lack of efficient approaches to generate large numbers of therapeutic grade retinal cells for transplant. This project will develop an optimized procedure for the efficient induction and enrichment of human rod photoreceptors and RPE from stem cells and fibroblasts using small molecules and reprogramming strategies. Our group will develop and test novel biomaterials enhanced with photoreceptor survival factors and compare the survival and functional engraftment potential of single and combinatorial photoreceptor/RPE delivery on cone survival and function in animal models of late stage RP. This research will provide solutions for cell therapy safety and allograft immune tolerance.
What happens to cells injected in the knee of osteoarthritis patients?
Sowmya Viswanathan, Krembil Research Institute ($100,000)
Jas Chahal, Toronto Western Hospital
Ali Naraghi, University Health Network
Osteoarthritis (OA) is a common joint disease affecting 1 in 10 Canadians. It is a lasting condition in which cartilage breaks down, causing bones to rub against each other, resulting in stiffness, pain and loss of joint movement. Currently, there are few effective treatments available for patients suffering from osteoarthritis. MesenchymalStromal Cells (MSCs) are cells that can be obtained from bone marrow and other tissues. They reduce pain, inflammation and help with regenerating the cartilage. Although 18 global small clinical trials have been completed, questions regarding dose, timing of injection, route of administration and mechanism of MSCs still persist. Our research team has pioneered Canada’s OA trial using autologous MSCS. Early results show that the MSCs are safe, and have an effect in terms of pain and function. However, individual differences were observed between patients. There may be multiple reasons for these differences, including the quality and potency of the MSCs and their joint localization and interaction with local inflammatory cells. To address this gap in knowledge, this study will use a uniform, pre-selected MSC donor that is labelled with iron nanoparticles so they can be tracked once injected into patient knees by magnetic resonance imaging (MRI). This will tell us where the MSCs go in the joint, whether they to go to sites of inflammation, how many cells remain immediately, and a month after injection. Using this information, we can see how the localization and duration of MSCs in the joint correlates with the patient’s pain, quality of life, symptoms scores, and with changes in inflammation and inflammatory macrophages.
A trial to improve wound healing using stem cells from patient’s own discarded burned tissue.
Marc Jeschke, Sunnybrook Research Institute ($100,000)
The single most important factor that determines survival of a burn patient is wound healing. Our team recently isolated cells identified as burn-derived mesenchymal stem cells (BD-MSCs) from discarded burned skin. We then developed Integra®-SC a skin substitute that was engineered by incorporating BD-MSCs into Integra®, and found beneficial results in both small and large animal models. In this study, we will conduct a first-in-humans clinical trial at an academic hospital in Ontario. We will use Integra®-SC, developed from a patient’s own surgically removed burned tissue, to place on their excised burn wounds. We believe that Integra®-SC will facilitate and improve wound healing, heal faster, and, in the long-term, result in less scar formation. Utilizing Integra®-SC we can avoid surgically removing a patient’s own good uninjured skin to use as a donor tissue. After safety analyses, we will evaluate any needs or gaps in order to include recruitment of patients with a larger percent total body surface area burn. Integra®-SC has a broad clinical application and could impact the larger burn community, patients with traumatic and complex wounds, and the stem cell research community, creating a new standard for the way we care for patients in the province of Ontario and world-wide.
- A stem cell approach to regenerate the injured spinal cord ($400,000) Project Leader: Michael Fehlings (University Health Network)
- Cellular Immunotherapy for Septic Shock ($400,000) Project Leader: Duncan Stewart (Ottawa Hospital Research Institute)
- Towards a cell therapy application for using pluripotent stem cell-derived cardiomyocytes to treat cardiovascular disease ($250,000) Project Leader: Gordon Keller (University Health Network) –
- Cone photoreceptor derivation and transplantation – an innovative approach for the treatment of age-related macular regeneration ($250,000) Project Leader: Valerie Wallace (University Health Network) –
- Application of novel stem cell derived human non-monocytic dendritic cell precursors (hNM-DCPs) for immunotherapies ($250,000) Project Leader: Mick Bhatia (McMaster University)
- Preclinical evaluation of a bioengineered human islet ($100,000) Project Leader: Cristina Nostro (University Health Network)
- Overcoming central vision loss with stem cell therapy and rehabilitation ($100,000) Project Leader: Valerie Wallace (University Health Network
- Pluripotent and cord blood derived progenitor t-cells for immune reconstitution therapy ($100,000) Project Leader: JC Zuniga-Pflucker (Sunnybrook Research Institute)