Medicine by Design–OIRM New Ideas, 2017

The following projects received awards from a 2017 New Ideas program co-funded by Medicine by Design and the Ontario Institute for Regenerative Medicine:

The impact of environmental pollutants on pancreas development

Project Leader:  Jennifer Bruin (Carleton University)

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.

A 3D model of muscle to study potential therapies for Duchenne muscular dystrophy

Project Leader: Penney M. Gilbert (University of Toronto)

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.

Tailoring donor lungs to control immune response before transplant

Project Leader: Stephen C. Juvet (University Hospital Network)

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.

Improving the creation of bile duct cells to model liver disease

Project Leader: Binita M. Kamath (SickKids Research Institute)

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.

A computational modelling platform to support imaging and tissue design

Project Leader: John Parkinson (SickKids Research Institute)

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.

Understanding radial glial cell response to neural injury at a single cell level

Project Leader: Bret Pearson (SickKids Research Institute)

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.

A therapeutic strategy for treating Duchenne muscular dystrophy

Project Leader: Michael A. Rudnicki (Ottawa Hospital Research Institute)

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 dystrophic 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.

Magnetic resonance imaging to assess stem cell treatments for lung disease

Project Leader: Giles Santyr (SickKids)

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.

Autism spectrum disorder drug testing using human neurons

Project Leader: Karun Singh (McMaster University)

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.

Clinical investigation of cell therapy to treat age-related osteoporosis

Project Leader: William L. Stanford (Ottawa Hospital Research Institute)

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.

Making new blood vessels for life-threatening lung diseases in newborns

Project Leader: Bernard Thébaud (Ottawa Hospital Research Institute)

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.

New ways to stimulate the production of insulin-producing cells to treat diabetes

Project Leader: Michael B. Wheeler (University of Toronto)

Diabetes, a disease affecting approximately 1 in 10 Canadians is characterized by insufficient insulin secretion to control blood sugar. Although there are a multitude of drugs to treat diabetes, serious heath complications persist, leading to unwanted suffering and premature death. In type 1 diabetes (T1D), islet transplantation has opened up new avenues of treatment; however, due to donor organ shortages, it is not a viable treatment for the ~350,000 people in Canada with this disease. 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.