OIRM's research program includes large, disease-based team grants, smaller New Ideas grants to answer basic research questions and Post-doctoral Fellowships. Click on the links below to view summaries of current projects.
FUNDED DISEASE TEAM PROJECTS
- Heart regeneration with stem cell-derived heart muscle cells ($750,000; project renewed from 2016)
Project Leader: Michael Laflamme (University Health Network)Description: After heart attack, heart muscle is replaced by scar tissue, often initiating progressive heart failure. Current options for treatment are limited, and it remains a disease with high morbidity, mortality and societal costs. The ability to “remuscularize” the damaged zone by transplanting cardiomyocytes (heart muscle cells) grown from human embryonic stem cells (hESCs) represents a potentially revolutionary new therapy for patients suffering from this disease. This project brings together a diverse team of investigators with expertise in stem cell and developmental biology, cell transplantation, cardiac imaging and large-animal models of heart attack and the surgical care of patients with end-stage ischemic heart disease to: 1) develop a scalable, clinical-grade product comprised of hESC-derived ventricular myocytes; and 2) show that this cell product can stimulate proper heart function and remuscularize the infarct scar in a pig model. With the successful completion of this preclinical work, we will submit a clinical trial application to launch an Ontario-based, first-in-humans trial of hESC-derived ventricular myocytes as a cell-based therapy for heart failure..
- Repairing white matter in the brain following disease or injury in children or teenagers ($750,000; project renewed from 2016)
Project Leader: Freda Miller (SickKids Research Institute)Description: 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. This accomplished team of basic researchers and clinician-scientists aims to change this situation by enhancing the growth of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. Our brains contain resident neural precursor cells (NPCs; a type of stem cell) that normally make oligodendrocytes, and the team will investigate whether these cells can be activated with drugs to promote repair. In earlier studies, this team discovered that a widely-used and safe drug, metformin, can enhance the formation of oligodendrocytes from NPCs and can promote recovery following pediatric brain injury. This project will translate this finding to the clinic, with the ultimate goal of a pilot clinical trial for metformin in children and adolescents with white matter damage. The study will include preclinical work in different mouse models of white matter damage and will develop protocols to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, the team will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately a combined approach will be used to treat white matter damage in humans. This work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
- Cellular Immunotherapy For Septic Shock (CISS): Translational research for a Phase II trial and beyond ($750,000)
Project Leader: Lauralyn McIntyre (Ottawa Hospital Research Institute)
Description: Septic shock is a devastating illness and the most severe form of infection seen in the intensive care unit (ICU). Approximately 20 – 40% 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, at a cost of approximately $4B in Canada annually. Mesenchymal stem cells (MSCs) represent a novel treatment, and have been shown to control the immune system, increase clearance of bacterial pathogens, restore organ function, and reduce death in preclinical models.
Over the last five years, this multi-disciplinary team has led the development of a research program studying MSCs in septic shock and was the first in the world to have conducted a Phase I clinical trial that evaluated MSCs in patients with septic shock. This trial established that MSCs appear safe and that a randomized controlled trial is feasible. Based on these results, the team is now moving to a larger, Phase II clinical trial at several academic hospitals across Ontario and Canada that 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. Positive results from this study will provide the impetus and justification to proceed to a Phase III international trial. This team grant will also provide funding to optimize a cryopreserved MSC product, identify bio-signatures tailored to septic shock, and to develop MSC modifications to improve their performance in future septic shock clinical trials.
- INCuBATOR: New cell treatments for lung injury in premature infants ($528,351)
Project Leader: Bernard Thébaud (Ottawa Hospital Research Institute)Description: Extreme prematurity is the main cause of mortality and morbidity in children before five years of age. The most severe complication is bronchopulmonary dysplasia (BPD), a chronic lung disease that follows ventilator and oxygen treatment for acute failure to breathe. BPD also adversely affects the brain and leads to blindness. Currently, there is no treatment for BPD. Because these injuries occur in developing organs, consequences are life-long and carry a high economic burden. Thus, effective interventions at this stage of life provide exceptional value.
Bringing new treatments into patients, especially sick newborns, is time-consuming, expensive and often fails. This team of researchers and clinician-scientists was the first to show that mesenchymal stem cells from the umbilical cord (UC-MSC) can repair lung injury in rodents. The team has also developed a highly efficient system that yields high numbers of clinical grade UC-MSCs that will be tested in a unique large animal model that closely mimics the human disease. In preparation for a Phase I human clinical trial, the team will also: 1) perform rigorous reviews of research using MSCs to treat BPD in animals as well as using MSCs in in preterm infants, 2) interview parents of preterm infants, physicians and researchers to ascertain their views on the conduct of stem cell trials in newborns, 3) conduct an economic evaluation to ensure that MSC therapy for BPD is economically viable, and 4) determine the feasibility of eligibility criteria, outcome measures and final protocol of the clinical trial. Thus, the INCuBATOR project will accelerate the translation of a potential breakthrough therapy that will improve the outcome of extreme preterm babies in Canada and world-wide.
Cell transplantation to restore vision ($275,000)
Project Leader: Valerie Wallace (University Health Network)
Description: Age related macular degeneration (AMD) is a degenerative disease that robs patients of central vision, due to the loss of light-sensitive cone photoreceptors and their support cells, the retina pigmented epithelium (RPE) in the retina. RPE transplantation alone, currently in clinical trials, is not sufficient to reverse vision loss after cone degeneration as lost photoreceptors cannot regenerate. Photoreceptor transplantation is thus also necessary. This project will combine expertise in stem cells, retinal development, biomaterials, vascular biology, gene regulation and ‘safe-cell’ therapies to establish a transplantation paradigm to restore vision loss associated with AMD. The team will 1) develop a procedure for the efficient creation and enrichment of human cone photoreceptors and RPEs using small molecules and reprogramming strategies, 2) determine the optimal conditions for engraftment into blind hosts, and, 3) evaluate the effects of engraftment and function. To achieve these goals the team will exploit advances made by team members: superior cone reporter and AMD-relevant mouse models, methods for inducing cone photoreceptors from pluripotent and somatic stem cells, and a new cone biomaterial delivery system that promotes cone survival and integration.
- 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)
FUNDED NEW IDEAS PROJECTS
2017-2018 Awardees (*co-funded by Medicine by Design; **Funded by Medicine by Design):
1. The impact of environmental pollutants on pancreas development ($75,000) Project Leader: Jennifer Bruin (Carleton University)
Description: Diabetes is caused by a deficiency in insulin-secreting pancreatic beta cells, which cannot be sufficiently explained by genetics. Exposure to environmental chemicals is associated with increased diabetes risk, but the direct effects of environmental pollutants on beta cells are only beginning to emerge. This project will examine the impact of a specific environmental pollutant called ‘TCDD’ on early pancreas development, a particularly sensitive time for environmental exposures. TCDD is known to turn on enzymes that are responsible for detoxifying environmental chemicals, but can also generate intermediate products that are often more toxic than the original chemical. This team recently showed that TCDD can activate these enzymes in adult pancreatic cells and predicts the process will be similar in the fetal pancreas, which may predispose exposed individuals to developing diabetes later in life. The team will evaluate the impact of maternal TCDD exposure on pancreas development in both a mouse model and in human embryonic stem cells cultured in the lab. This work will shed light on the impact of environmental chemicals on pancreas development and the rising incidence of diabetes worldwide.
2. A 3D model of muscle to study potential therapies for Duchenne muscular dystrophy* ($75,000) Project Leader: Penney M. Gilbert (University of Toronto)
Description: Motor neurons are cells that transmit electrical signals from the brain to skeletal muscle cells to enable human functions such as walking, swallowing and breathing. The position on muscle fibers where motor neurons attach is referred to as the neuromuscular junction (NMJ). Although it is accepted that the NMJ is vital to skeletal muscle function and health, it is difficult to study the role of NMJ activity on healthy or diseased human skeletal muscle in part due to a lack of appropriate culture methods. To overcome this technical hurdle, this team has engineered a 3D model of human skeletal muscle tissue containing motor neurons that produce muscle cell contractions when exposed to stimuli. Many replicate tissues can be created from this miniaturized platform, which is important when performing research studies with precious human biopsy samples. The project’s goal is to use this pre-clinical tool to study the human NMJ in the context of Duchenne muscular dystrophy (DMD). Patients with DMD harbor a mutation in a gene that contains the instructions to produce a protein called dystrophin. Dystrophin is situated near the NMJ in skeletal muscle cells, but it is not clear whether it is involved in regulating NMJ activity. With this 3D culture platform, the team will examine roles for the NMJ in DMD disease progression and evaluate the impact of clinically approved drugs that modify NMJ activity as a possible treatment for DMD patients.
3. Tailoring donor lungs to control immune response before transplant** ($75,000) Project Leader: Stephen C. Juvet (University Hospital Network)
Description: Lung transplantation is the only treatment that can prolong the lives of patients with end-stage lung diseases. Unfortunately, long-term outcomes remain poor, with just over half of recipients surviving five years. The primary cause of death is chronic lung allograft dysfunction (CLAD), a scarring condition that results from damage caused by the recipient’s immune system. Available anti-rejection drugs are unable to prevent CLAD.
Regulatory T cells (Tregs) are specialized immune cells that can control harmful immune responses and are able to enter transplanted organs to create a state of local immune control. Ex vivo lung perfusion (EVLP) is a technique that allows donor lungs to be evaluated for quality outside the body and can also be used to administer treatments. This team will use EVLP in a rat model to assess whether seeding the donor lungs with Tregs before transplantation can create an environment in the lung that, after transplantation, will prevent harmful rejection responses. If successful, the team will test this therapy in discarded human donor lungs and ultimately in a Phase I clinical trial in human lung transplantation.
4. Improving the creation of bile duct cells to model liver disease** ($75,000) Project Leader: Binita M. Kamath (SickKids Research Institute)
Description: Bile duct disorders comprise a substantial unmet burden of disease, have no effective treatment, and account for a significant proportion of liver transplants. A better understanding of the underpinnings of these disorders would provide opportunities to develop medial interventions. Current methods to create bile duct cells (cholangiocytes) from human induced pluripotent stem cells (hiPSCs) represent a significant advance, however, the resulting cells do not fully mimic natural development or function. This project aims to address this gap by exposing hiPSC-derived cholangiocytes to concentrations of bile acids, multi-functional molecules that normally bathe cholangiocytes in the body. It is anticipated that replicating the normal lab culture milieu with bile acid mixtures will enhance cholangiocyte maturation and function. These physiologically-optimized cholangiocyte cultures can then be used to identify pathways for normal development and serve as a platform to research drug targets that might treat genetic and acquired biliary diseases.
5. A computational modelling platform to support imaging and tissue design** ($75,000) Project Leader: John Parkinson (SickKids Research Institute)
Description: Tremendous progress has been made in the design of cell-based systems that offer therapeutic opportunities in a wide variety of tissues such as lung, intestine, pancreas and heart. To provide molecular level insights into the organization and coordination of these systems, computer modeling platforms are required capable of capturing the temporal and spatial dynamics of the proteins and pathways involved. This project aims to deliver a 4D simulation environment – 4DCell -- to model complex cellular behavior, such as the influence of spatial relationships on the function of biochemical pathways. One of the outcomes of 4DCell will be the provision of a powerful platform for dissecting the signaling networks that drive the development of intestinal organoids.
6. Understanding radial glial cell response to neural injury at a single cell level** ($75,000) Project Leader: Bret Pearson (SickKids Research Institute)
Description: Unlike most tissues in the human body, the loss of central nervous system (CNS) tissue due to acute injury or disease is usually irreparable, resulting in chronic disability for individuals and associated annual health care costs in the hundreds of billions of dollars. Regenerative medicine holds the promise of treating CNS injury, but current clinical trials for CNS injuries are focused almost exclusively on cellular transplants. To date, there has been no approved treatment using the transplant method prompting calls for new approaches to treat CNS injuries. To help drive these new approaches, we first require a better understanding of the molecular events occurring during regeneration, which can only be achieved through model systems. In contrast to humans and other mammals, zebrafish can regenerate and functionally recover photoreceptors in the retina of the eye as a result of acute injuries through the action of specialized radial glial (RG) cells, which are the resident stem cells of the mature CNS. This project will take advantage of this natural regenerative capacity to produce the first complete description of how global gene expression changes in RG cells in response to a lesion, at single cell resolution. We will identify new and critical genetic pathways in this process that will directly inform how human RG cells can be manipulated to facilitate CNS regeneration as a therapy for acute injury and disease.
7. A therapeutic strategy for treating Duchenne Muscular Dystrophy ($75,000) Project Leader: Michael A. Rudnicki (Ottawa Hospital Research Institute)
Description: Duchenne Muscular Dystrophy (DMD) is a devastating genetic muscular disorder of childhood manifested by progressive debilitating muscle wasting and ultimately death around the second decade of life. It affects 1 in 3,500 newborn boys, with 20,000 new diagnoses every year. No effective therapies are currently available. This project will further explore the role of a protein, Wnt7a, which this team discovered stimulates the expansion of muscle stem cells in mice, and improves muscle regeneration upon local treatment. However, a significant limitation of Wnt7a is that it cannot be delivered systemically via the circulation to treat muscle across the body. To overcome this limitation, this team will design a drug delivery system to allow targeting of the entire skeletal muscular system via the circulation. Experiments as part of this project will also provide greater understanding that could significantly increase the therapeutic potential and efficiency of Wnt7a for treating DMD, especially when used in combination with gene correction therapies.
8. Magnetic resonance imaging to assess stem cell treatments for lung diseasel** ($75,000) Project Leader: Giles Santyr (SickKids Research Institute)
Description: Chronic and early lung diseases exact a tremendous toll on society, affecting 2.5 million people in Ontario alone. There is a need for new treatment approaches that not only arrest lung disease, but reverse it. A promising approach is the introduction of stem cells into the lung that facilitate the repair of damaged tissue. However, development of effective stem cell treatments is hampered by an inability to assess where in the lung the stem cells go and whether they are working or not. Magnetic resonance imaging (MRI) can potentially address these limitations as it can visualize specific tissues and does not involve radiation. This enables MRI to be used safely to monitor stem cell therapies over time, particularly important in children. One of the most exciting recent developments is the use of iron tagging that enhances the ability of MRI to detect and monitor specific cells. Iron tagging has been used to visualize stem cells in various organs, but has traditionally been challenging to use in the lung due to low signal. This has changed with the recent development of new hyperpolarized MRI approaches that substantially boost lung MRI signal. The objective of this project is to combine hyperpolarized MRI with iron tagging to visualize stem cells introduced within the lungs of rats. The development of sensitive MRI methods to assess stem cells in the lung will enable testing of new treatments in animal models of lung disease for eventual translation to the clinic.
9. Autism spectrum disorder drug testing using human neurons ($75,000) Project Leader: Karun Singh (McMaster University)
Description: Autism spectrum disorders (ASD) are a health and financial burden to Ontario because there are no medications that treat the core symptoms of disease. To overcome this, it is necessary to identify new compounds that can move to clinical trials. Ideally, drug testing should be done on accurate models of disease so that compounds have the best chance of working in patients. This team has established a pipeline between McMaster University and SickKids Hospital to genetically engineer human induced pluripotent stem cells, and rapidly produce and phenotype human neurons by directed differentiation. The research will use this approach to test a new ASD risk gene for candidate drug testing in human neurons. If successful in identifying candidate drugs, this will be a major achievement that can move forward with existing partnerships towards a pilot clinical trial. It will also lay the groundwork for future drug screening using FDA-approved compound libraries in a high-throughput format, allowing the team to establish the first ASD drug screening platform in Canada.
10. Clinical investigation of cell therapy to treat age-related osteoporosis ($75,000) Project Leader: William L Stanford (Ottawa Hospital Research Institute)
Description: Osteoporosis underlies more than 200,000 fragility fractures in Canada each year, costing $3.9 billion dollars annually. Age-related osteoporosis affects both men and women and is caused by decreased bone formation resulting from a loss of bone stem cells found in the mesenchymal stromal cell (MSC) population. Therapeutics that directly target age-related osteoporosis are limited, and often don’t increase bone formation. Recently, this team showed that a single systemic MSC transplant enriched with skeletal stem cells (SSCs) prevents the onset of age-related osteoporosis in mice. Will this work in humans? If it does, it could be a cost-effective strategy to improve the quality of life in hundreds of thousands of Canadians. Since MSCs are being used in hundreds of clinical trials, that have demonstrated safety of these cells, there is no urgent need for new clinical trials specifically for osteoporosis at this time. Instead, this team will use clinical samples from an ongoing MSC trial in elderly patients being performed at the University of Miami and assess them for changes in bone metabolism and evidence of increased bone formation. In this way, the team can determine whether there is clinical data to support using MSCs/SSCs to treat osteoporosis, which would validate the use of additional, targeted cell-based trials.
11. Making new blood vessels for life-threatening lung diseases in newborns ($75,000) Project Leader: Bernard Thébaud (Ottawa Hospital Research Institute)
Description: High blood pressure in the lungs (pulmonary hypertension, PH) is a severe complication of lung disease in babies with overly small lungs. PH doubles the risk of death, and survivors have long-term health problems. Today, there is no treatment to make small lungs grow bigger or lower the incidence of PH. This project team was the first to show that endothelial progenitor cells (EPCs), by making new blood vessels in the lung, can make the lung grow and lower PH. EPCs can replace diseased endothelial cells, but they are more likely to produce many factors inside tiny particles (exosomes) in the right amount and at the right time so that new blood vessels can grow. These cells can be seen as “smart local pharmacies” that regulate appropriate blood vessel growth. This project will test the safety and efficacy of umbilical cord blood EPCs in experimental neonatal PH. If successful, this research will bring a breakthrough treatment for PH that may also benefit patients with other cardiovascular diseases, heart attack, stroke or preeclampsia.
12. New ways to stimulate the production of insulin-producing cells to treat diabetes* ($75,000) Project Leader: Michael B. Wheeler (University of Toronto)
Description: Diabetes, a disease affecting approximately 1 in 10 Canadians is characterized by insufficient insulin secretion to control blood sugar. Recent studies have demonstrated it is possible to generate an unlimited source of insulin-producing cells from stem cells, leading to intensive efforts to make insulin cell replacement therapy a reality. Despite promising results, significant limitations still exist. One major hurdle is an inability of the insulin-secreting cells grown in the lab to connect with the elaborate natural insulin cell network in the pancreas. This project proposes that drugs to enhance the production of new insulin cells is a much more feasible approach to treat diabetes. The team has shown that a natural chemical, GABA, increases insulin cell quantities in mice and will investigate whether GABA could be used as a drug to promote the production of insulin cells in the body. Several experiments are planned to better understand how GABA promotes insulin cell production using mouse models. The team will then test the ability of GABA to reverse diabetes in mice and provide initial proof that GABA works to enhance insulin cell production in humans.
Past Awardees (*co-funded by Medicine by Design):
- Control of immune tolerance toward allograft cell transplants ($50,000) Project Leader: Andras Nagy (The Lunenfeld-Tanenbaum Research Institute) 2015-16
- Dissolving scar tissue in spinal cord injuries improve candidacy and effects of stem cell transplants* ($49,988) Project Leader: Charles Tator (University Health Network) 2015-16
- Sole fuel source to enhance pluripotency ($50,000) Project Leader: Dean Betts (Western University) 2015-16
- An injectable biomaterial system for the delivery of stem cells in the treatment of retinal disease ($50,000) Project Leader: Heather Sheardown (McMaster University) 2015-16
- Activating enhancers to improve reprogramming efficiency* ($50,000) Project Leader: Jennifer Mitchell (University of Toronto) 2015-16
- Better maturation of iPS-derived heart cells ($49,200) Project Leader: John Coles (SickKids Research Institute) 2015-16
- Protein inactivation by agrochemicals as a mechanism underlying development of Autism Spectrum Disorder ($49,994) Project Leader: John Vessey (University of Guelph) 2015-16
- Injectable, tissue engineered scaffold for delivery of cardiac patches* ($50,000) Project Leader: Milica Radisic (University of Toronto) 2015-16
- Heart tissue repair via immune cell growth factors* ($50,000) Project Leader: Slava Epelman (University Health Network) 2015-16
- Intestinal stem cells and gut microbiota in early postnatal development and necrotizing enterocolitis ($49,980) Project Leader: Tae-Hee Kim* (SickKids Research Institute) 2015-16
- Biomimetic surfaces for directed differentiation of lung stem cells * ($49,983) Project Leader: Tom Waddell (Univerisity Health Network) 2015-16
- Mechanisms regulating differentiation in hemangioma stem cells ($49,500) Project Leader: Zia Khan (Western University) 2015-16
- TIMP-engineered niches for liver progenitor cell expansion ($75,000) Project Leader: Rama Khokha (University Health Network) 2014-15
- Control of RNA translation into proteins in human stem cells, neurons and disease ($75,000 )Project Leader: James Ellis (SickKids Research Institute) 2014-15
- Engineering a functional human thymus from pluripotent stem cells ($75,000) Project Leader: Peter Zandstra (University of Toronto) 2014-15
- Role of short RNA fragments in mediating the anti-inflammatory effects of bone marrow stem cells in sepsis ($75,000) Project Leader: Duncan Stewart (Ottawa Hospital Research Institute) 2014-15
- Genomic correction of cardiac sarcomeric protein mutations in iPSC-derived cardiomyocytes ($75,000)Project Leader: John Coles (SickKids Research Institute) 2014-15
FUNDED POST-DOCTORAL FELLOWSHIP PROJECTS
2017-2019 (co-funded by Medicine by Design):
Rescuing vision in models of retinal degeneration Project Leader: Arturo Ortin-Martinez, University Health Network (Valerie Wallace lab)
Developing an immune-cell approach to cardiac regeneration Project Leader: Yiming Wang, University Health Network (Slava Epelman lab)