Current Research

FUNDED DISEASE TEAM GRANT PROJECTS

2015-2016 Awardees:

  1. Heart regeneration with stem cell-derived heart muscle cells ($400,000 with possibility of added funds after year 1)
    Project Leader:
     Michael Laflamme (University Health Network)
    Description: After a heart attack, damaged heart muscle is replaced by scar tissue, often initiating progressive heart failure. Our current options for treatment are limited, and this remains a disease with high morbidity, mortality and societal costs. The ability to “remuscularize” the damaged tissue by transplanting heart muscle cells made from human embryonic stem cells represents a potentially revolutionary new therapy for patients suffering from this disease. This project will generate the required heart muscle cells to be well-characterized, highly scalable, and clinical-grade, and conduct necessary tests in a pig model to determine if the transplantation successfully remuscularizes the infarct scar and improves contractile function.
    Projected Outcomes: The overall goal of this project is to use pluripotent heart muscle stem cells to regenerate areas of damage after a heart attack, and the proposed preclinical studies are intended to provide the safety and efficacy data required to initiate a first-in-human clinical trial.  
     
  2. Repairing white matter in the brain following disease or injury in children or teenagers ($400,000 with possibility of added funds after year 1)
    Project Leader:
     Freda Miller (SickKids Research Institute)
    Description: The neural circuits in our brains require a layer of insulation in order to transmit signals in a rapid and efficient fashion. This insulation is called white matter and is comprised of a specific type of brain cell called an oligodendrocyte. Damage to brain white matter occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. This project will use a widely-used and safe drug, metformin, which they discovered can encourage brain stem cells to make new oligodendrocytes following brain injury. The team will perform preclinical work in mouse models while developing approaches to measure the efficacy of metformin in children and adolescents with white matter damage. At the same time, they will search for additional methods of activating brain stem cells to make oligodendrocytes, with the idea that a combinatorial approach will be used to treat white matter damage in humans. The team will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. 
    Projected Outcomes: Finding that brain stem cells can be activated for white matter repair would lead to a dramatic shift in the how we treat neurological injury and disease and would advance the development of rigorous clinical trials for white matter repair in humans.
     
  3. A stem cell approach to regenerate the injured spinal cord ($400,000 with possibility of added funds after year 1)
    Project Leader: Michael Fehlings (University Health Network)
    Description: One of the main hurdles in regenerative therapy for spinal cord injury (SCI) is the very low intrinsic ability of the nervous system to repair itself. The promise of neural stem cell transplantation lies in its ability to replace neurons and glia lost due to traumatic injury. However, there remain critical shortfalls, including a lack of stem cells with an ability to survive post-transplant, an inhibitory environment in the injured spinal cord, and a lack of clinical models to conduct research.  This project will test neural cells made from induced pluripotent stem cells in combination with bioengineered interventions aimed at overcoming the inhibitory environment and enhancing migration survival of transplanted cells at the site of injury. 
    Projected Outcomes: Demonstrated recovery in animal models using the neural stem cells and bioengineered approach, sufficient to develop a clinical trial protocol. This work also has excellent potential for commercialization of novel technologies developed as part of the proposed experiments. 
     
  4. Cellular Immunotherapy for Septic Shock ($400,000 with possibility of added funds after year 1)
    Project Leader:
     Duncan Stewart (Ottawa Hospital Research Institute)
    Description: Mesenchymal stem cells (MSCs) represent a promising treatment for septic shock, the most severe form of infection. Despite the administration of fluids and antibiotics, almost half of patients with septic shock will die due to severe inflammation and multiple organ failure, and survivors suffer long-term physical dysfunction and reduced quality of life. This team is currently conducting the world’ first-in-human clinical trial, “Cellular Immunotherapy for Septic Shock” (Phase I CISS Trial), at the Ottawa Hospital to examine the safety and to determine the optimal dose of MSCs for the treatment of patients with septic shock. In preparation for larger Phase II and Phase III clinical trials, this project seeks to refine the CISS cellular products to ensure sufficient quantities can be made to supply the hospitals in the upcoming trials, maintain their safety, quality, and potency, while remaining particularly mindful of containing the product manufacturing costs.  
    Projected Outcomes: Over the next five years, the CISS clinical trials (Phase II and III) will have a tremendous impact on the lives, physical function, and quality of life of the people of Ontario and beyond, through the development of a novel therapeutic for septic shock, a devastating clinical problem that is currently associated with a high risk of death and substantial long term morbidity for survivors.


List of Reviewers

 

2014-2015 Awardees:

  • Project Leader: Gordon Keller (University Health Network) - Towards a cell therapy application for using pluripotent stem cell-derived cardiomyocytes to treat cardiovascular disease ($250,000)
     
  • Project Leader: Valerie Wallace (University Health Network) - Cone photoreceptor derivation and transplantation - an innovative approach for the treatment of age-related macular regeneration ($250,000)
     
  • Project Leader: Mick Bhatia (McMaster University) - Application of novel stem cell derived human non-monocytic dendritic cell precursors (hNM-DCPs) for immunotherapies ($250,000) 
     

 

FUNDED ACCELERATOR GRANT PROJECTS

2015-2016 Awardees:

  1. Preclinical evaluation of a bioengineered human islet ($100,000)
    Project Leader:
     Cristina Nostro (University Health Network)
    Description: The key objective of this study will be to recreate the pancreatic islet niche to optimize survival, integration with the host and maturation of pancreatic endocrine cells. In order to recreate a fully functional niche, pancreatic cells will be transplanted with accessory cells, such as microvessels and neural cells. 
    Projected Outcomes: Significant advances in the understanding of transplantation of hESC-derived pancreatic progenitors and β-like cells with an improved niche in a collagen device.   
     
  2. Overcoming central vision loss with stem cell therapy and rehabilitation ($100,000)
    Project Leader:
     Valerie Wallace (University Health Network)
    Description: This project will develop cone photoreceptor transplantation as a treatment for cone degeneration, for which cures are currently unavailable. Induction of robust cone differentiation from human pluripotent cells and demonstrating cone-mediated improvement in retinal function in transplanted mice will address the feasibility of this therapeutic approach. 
    Projected Outcomes: Demonstrate greater than 90% induction of cone photoreceptors, and enhance engraftment of GFP-tagged mouse cones to blind hosts using innovative biomaterials strategies, immune suppression and cell enrichment.  
     
  3. Pluripotent and cord blood derived progenitor t-cells for immune reconstitution therapy ($100,000)
    Project Leader: Juan-Carlos Zúñiga-Pflücker (Sunnybrook Research Institute)
    Description: The goal is to develop clinically applicable protocols for the generation of pro-T cells from different stem/progenitors using inductive biomaterials and soluble Notch ligands, to compare yield, functionality and cost of generating pro-T cells with respect to both cell source (hPSC- vs CB-derived) and induction protocol (inductive biomaterial vs. soluble Notch) and to demonstrate function of these pro-T cells in a mouse pro-T cell maturation model.
    Projected Outcomes: Firstly, to create one or more OP9 stromal-free protocol(s) for in vitro pro-T cell production, and optimize protocol, with respect to cost, yield and efficiency, for clinically applicable production of pro-T cells with demonstrated capacity to restore thymic function in vivo.

 

FUNDED NEW IDEAS GRANT PROJECTS

2015-2016 Awardees (*co-funded by Medicine by Design):

  1. Project Leader: Andras Nagy (The Lunenfeld-Tanenbaum Research Institute) - Control of immune tolerance toward allograft cell transplants ($50,000)
    Description: Rejection of allogeneic (from a donor) transplanted cells by the recipient’s immune system remains a major hurdle for next-generation therapies. Current anti-rejection therapies rely on drugs that can be highly variable in effect and often have severe side effects.  This project will create a gene delivery system that can be introduced into therapeutic cells that will endow them with two transformative elements: a system that “hides” the cells from elimination by the immune cells of a foreign host, and a controllable ON/OFF switch that can be used to withdrawal the immune-evasion systems, providing a way to clear grafted cells when they are no longer needed. 
    Projected Outcomes: Immune-evasion delivery tools to support the success of therapeutic cells grafts by increasing immune tolerance and increasing the range of applications for which they will be feasible.
     
  2. Project Leader: Charles Tator* (University Health Network) - Dissolving scar tissue in spinal cord injuries improve candidacy and effects of stem cell transplants ($49,988)
    Description: Stem cells from the brain or spinal cord are currently used in clinical trials in patients with chronic spinal cord injury (SCI). However, only a small number of patients have been treated, and the outcome is uncertain. The presence of scar tissue at the site of injury may prevent effective regrowth of nerve fibers, thus dissolving the scar may improve the effects of subsequent stem cell transplants. An enzyme named chondroitinase has been available for the past 15 years and has shown very favorable experimental results in experimental SCI. However, there has been no practical and safe way of giving this enzyme to patients with SCI.  This team has invented a new form of this enzyme which lasts more than one week and can be administered safely and effectively, without the need for direct injection or indwelling catheters and pumps. This project will test this enzyme in a rat model of cervical SCI. The technology for making this enzyme in clinical amounts and to clinical standards is already accomplished, and so there is definite potential for use of this agent in humans and commercialization.
    Projected Outcomes: Development of a practical strategy for delivering an enzyme to dissolve the scar tissue that forms in the spinal cord after injury, which is essential for making stem cell transplantation effective in humans with spinal cord injury.
     
  3. Project Leader: Dean Betts (Western University) - Sole fuel source to enhance pluripotency ($50,000)
    Description: Low efficiency and quality of induced pluripotent stem (iPS) cell generation is a significant disadvantage for potential clinical application. Increasing evidence implicates cellular metabolism in establishing distinct stem cell states. This project will advance the hypothesis that metabolic reprogramming enhances the generation efficiency of cells towards a naïve pluripotent stem cell state. The team will direct fibroblasts towards a single and/or bivalent metabolic states using sole fuel source selection to determine if their induction towards multiple pluripotent states is enhanced. The studies will develop a simple and reliable culture protocol to modulate the bioenergetic state of somatic cells to efficiently generate high quality naïve human iPS cells for future stem cell therapies.
    Projected Outcomes: The proposed research will improve the efficiency of generating high-quality human induced pluripotent stem cells by tailoring the fuel source and consequently driving the metabolism of somatic cells towards that found in pluripotent stem cells.
     
  4. Project Leader: Heather Sheardown (McMaster University) - An injectable biomaterial system for the delivery of stem cells in the treatment of retinal disease ($50,000)
    Description: The retina is a highly specialized tissue susceptible to a host of progressive, degenerative conditions that affect hundreds of millions of people worldwide. Available treatments for these diseases lack efficacy, reliability, accessibility, and patient comfort. Transplanted retinal pigment epithelial cells can contribute to the repair of damaged retinal pigment epithelial tissue, however inadequate cell delivery methods have resulted in low success rates, largely due to a lack of cell engraftment and survival. This lab has created a series of thermogelling injectable cell scaffolds that transition from liquid to gel at physiological temperatures. This project will study whether successful stem cell therapies to treat early disease stages in the retina can be realized in combination with these bioengineered scaffolds. It will begin with a modification of the polymer to further increase cellular attachment. Advanced in vitro investigations will be used to verify that the scaffold does not inhibit the ability of human embryonic stem cells to proliferate, and that the cells remain viable, and differentiate into retinal pigment epithelial cells. Finally, therapeutic stem cell-scaffold doses will be administered sub-retinally into a disease model to verify cell viability, engraftment and repair of damaged tissue.
    Projected Outcomes: The development of an injectable stem cell delivery platform that can increase the survival and engraftment of embryonic stem cells for the repair and regeneration of damaged retinal tissue.
     
  5. Project Leader: Jennifer Mitchell* (University of Toronto) - Activating enhancers to improve reprogramming efficiency ($50,000)
    Description: Regenerative medicine approaches ideally rely on the efficient generation of patient specific induced pluripotent (iPS) cells, however, this is impeded by the cost, time taken and the low efficiency of the reprogramming process. The expression of the Sox2 gene is a late, but required event in the reprogramming process and represents a barrier to reprogramming.  This project will establish a more effective reprogramming technique that can be applied to human patient-derived cells using CRISPR activation of reprogramming genes and their associated regulatory regions. The team will focus on activation of the endogenous Sox2 gene which currently presents a significant barrier to establishing fully reprogrammed cells. In addition, activation of Sox2 in the context of stem cell differentiation can improve the efficiency of neural differentiation. This work will later be expanded to include the regulatory regions for other genes that present barriers to reprogramming and may provide a faster and more efficient way to generate patient specific cells for personalized regenerative medicine.
    Projected Outcomes: Increased efficiency in generating patient specific iPS cells for regenerative medicine through epigenetic modulation.
     
  6. Project Leader: John Coles (SickKids Research Institute) - Better maturation of iPS-derived heart cells ($49,200)
    Description: Human cardiomyocytes (heart cells) can now be created from induced pluripotent stem cells with relative ease, however an unsolved issue is their immaturity such that they resemble fetal more than adult heart cells, which undermines their relevance to human diseases in many cases. This team has discovered a protein, referred to as ILK, which is responsible for maturation of heart cells in the normal developing heart and it will test utility of activating ILK as a new method to enable efficient maturation of the human cardiomyocyte in a dish.
    Projected Outcomes: This technology can improve the method for generating heart cells for research and therapeutics.
     
  7. Project Leader: John Vessey (University of Guelph) - Protein inactivation by agrochemicals as a mechanism underlying development of Autism Spectrum Disorder ($49,994)
    Description: While the ultimate cause of autism spectrum disorder (ASD) is still relatively unknown, there seems to be a combination of genetic and environmental conditions that influence the onset of disease. For example, several studies have found associations between pesticide exposure during pregnancy and the development of neurological symptoms. Recently, genetic studies have identified common cellular signals that are deactivated in most forms of ASD, identifying a cellular communication “hub” that seems to be off in the brains of ASD patients. A protein called MEF2C controls one of these communication hubs, and loss of MEF2C is believed to slow brain development and alter the types of neurons that are born. Recently, this team determined that two of the most common pesticides in use in Ontario inactivate MEF2C, preventing it from acting as a communication hub.  This project will determine if pesticide exposure at critical periods of pregnancy turns off MEF2C, impairs brain development, and leads to ASD symptoms. It will further investigate whether MEF2C projects from the effects of pesticides. Through examination of known genetic determinants as well as environmental triggers, this will expand our understanding of the link between development and neuropsychiatric symptoms.
    Projected Outcomes: If successful, this proposal will identify the mechanism by which pre-natal pesticide exposure triggers autism spectrum disorder and provide a target for therapeutic development.
     
  8. Project Leader: Milica Radisic* (University of Toronto) - Injectable, tissue engineered scaffold for delivery of cardiac patches ($50,000)
    Description: In the developed world, cardiovascular disease is responsible for the loss of more human lives than all cancers combined. Tissue engineering aims to regenerate or replace damaged tissues in an effort to improve the state of organ health. However, high-fidelity and structurally compatible tissue patches cannot be easily delivered to the body in a minimally invasive way. For delivery of a cardiac patch, open heart surgery is currently required.  This project proposes a system by which thick cardiac tissues may be delivered to the heart via injection. The team will design a biocompatible, shape-retaining, injectable, and self-assembling tissue scaffold that is based on two technologies previously developed in the Radisic lab. This scaffold will then be injected in vivo in a layer-by-layer approach, achieving the building up of tissue with organized structure in three dimensions.
    Projected Outcomes: Creation of a tissue scaffold compatible with minimally invasive delivery to the body to assemble cardiac patches in vivo. This technology would result in a facile, rapid, and cost-effective approach to production of functional and scalable heart tissues, and in a revolution in the clinical applications of tissue engineering.
     
  9. Project Leader: Slava Epelman* (Univerisity Health Network) - Heart tissue repair via immune cell growth factors ($50,000)
    Description: Very young hearts are able to fully regenerate after injury, while adult hearts cannot. In the young heart, this regeneration is dependent on primitive immune cells called macrophages that enter the heart during embryonic development. Importantly, these primitive macrophages are also found in the heart of adults (mice and humans). Following a heart attack in adult mice, primitive macrophage numbers are significantly reduced within the damaged zone of the heart. This project is focused on harnessing the regenerative properties of primitive cardiac macrophages. In the proposed studies, we will isolate primitive cardiac macrophages following a heart attack in mice and then determine which growth factors produced by these primitive macrophages promote important repair functions. If successful, future studies will focus on how we can deliver the identified growth factors to the injured heart in order to promote cardiac tissue repair.
    Projected Outcomes: We will define the growth factors produced by primitive macrophages that drive heart tissue regeneration following heart attack.
     
  10. Project Leader: Tae-Hee Kim* (SickKids Research Institute) - Intestinal stem cells and gut microbiota in early postnatal development and necrotizing enterocolitis ($49,980)
    Description: The intestine is a vital organ that absorbs nutrients and forms a physical barrier against the outside environment. The lining of the intestine is continuously self-renewed throughout life by stem cells located in the crypt, a pocket-like intestinal gland. At birth, newborns face dramatic environmental changes, among them the introduction of gut microbiota. Although proper intestinal development requires gut microbiota, its influence on intestinal stem cell maturation is unclear. Compromised intestinal development in newborns exposed at birth to the external environment leads to serious diseases, such as necrotizing enterocolitis (NEC), one of the most deadly gastrointestinal diseases in human infants. Currently, how NEC initiates is unknown. This project will investigate whether developmental defects in intestinal stem cells and their altered interaction with gut microbiota underlie the immature intestine and are responsible for NEC initiation. Using mice as a model system, the team will investigate signaling and transcriptional mechanisms of intestinal stem cell differentiation, as well as the role of gut microbiota during development.
    Projected Outcomes: This work will define the significance of intestinal stem cells and their differentiated cell populations in development and necrotizing enterocolitis (NEC), as well as identify new biomarkers for infant gut diseases. It will facilitate the development of intestinal stem cell based therapy for NEC.
     
  11. Project Leader: Tom Waddell* (Univerisity Health Network) - Biomimetic surfaces for directed differentiation of lung stem cells ($49,983)
    Description: Current systems for the study of lung epithelium are inadequate. Traditionally, alveolar epithelial cells (AECs) are grown on flat surfaces, which do not replicate the environment within the alveoli of the lung. Cells grown on decellularized scaffolds partially mimic AEC maturation, however, the complexity of decellularized scaffolds makes it difficult to identify and control the specific cues necessary to direct AEC development. This project has three goals. First, it will develop a simple, physiologically relevant cell culture system that better models the architecture of the alveolus. Second, it will study the capacity of lung stem cells to grow in these cavities and differentiate along an AEC lineage. Finally, it will produce a platform that also incorporates dynamic stretch, another physiologically relevant mechanical cue. Using this biomimetic construct, the team will assess maturation of lung stem cells in the presence and absence of stretch signals.
    Projected Outcomes: The proposed dynamic culture system will advance in vitro modeling of distal lung providing more suitable platforms for (1) disease modeling and evaluation of novel therapies, (2) patient-specific drug screening, (3) understanding cellular biology of airway epithelial cells, (4) modeling pulmonary cell-based therapeutic applications and (5) generation of more suitable cell sources for cell therapy.
     
  12. Project Leader: Zia Khan (Western University) - Mechanisms regulating differentiation in hemangioma stem cells ($49,500)
    Description: 
    Hemangiomas (commonly known as birthmarks) are tumours that arise from stem cells that mature abnormally and make blood vessels uncontrollably. These unique tumours appear soon after birth in 1 out of 100 newborns, grow rapidly, and then spontaneously disappear leaving a fatty deposit. As the only lab in Canada, and one of three in North America with a bank of hemangioma stem cells, this team has a rare opportunity to study how these cells maintain their stem cell properties and what causes them to mature into cells that make up blood vessels. The aim is to provide findings for blood vessel repair and regeneration that can be developed into faster and safer treatments for hemangioma patients.
    Projected Outcomes: Our research will identify potential targets for therapeutic vascular modulation in infantile hemangioma. Understanding the molecular intricacies in these cells has far-reaching implications for treating hemangiomas and other blood vessel-dependent diseases such as heart disease, diabetes, and cancers.

     

List of Reviewers
 

2014-2015 Awardees:

  1. Project Leader: Rama Khokha (University Health Network) - TIMP-engineered niches for liver progenitor cell expansion ($75,000)
     
  2. Project Leader: James Ellis (SickKids Research Institute) - Control of RNA translation into proteins in human stem cells, neurons and disease ($75,000)
     
  3. Project Leader: Peter Zandstra (University of Toronto) - Engineering a functional human thymus from pluripotent stem cells ($75,000)
     
  4. Project Leader: Duncan Stewart (Ottawa Hospital Research Institute) - Role of short RNA fragments in mediating the anti-inflammatory effects of bone marrow stem cells in sepsis ($75,000)
     
  5. Project Leader: John Coles (SickKids Research Institute) - Genomic correction of cardiac sarcomeric protein mutations in iPSC-derived cardiomyocytes ($75,000)