2019 CDTRP Research Innovation Grant Competition Results

The CDTRP is proud to share the results of the 2019 CDTRP Research Innovation Grant Competition and welcome 18 new projects into our national research structure.

This competition is made possible through the generous financial support, dedication and commitment from our national and regional partners, which include:

  • Addison Fund / Transplant Research Foundation of British Columbia (TRFBC)
  • Alberta Transplant Institute (ATI)
  • Ashley’s Angels
  • Canadian Liver Foundation (CLF)
  • Cystic Fibrosis Canada (CF Canada)
  • Kidney Foundation of Canada (KFOC)
  • Paladin Labs Inc. (Paladin)
  • SickKids Transplant & Regenerative Medicine Centre (SickKids)
  • Université de Montréal (UdeM)
  • University Health Network Multi-Organ Transplant Program (UHN)

Here are some quotes from our partners:

“Paladin Labs is proud to support innovative research aimed at improving transplant care” – Joseph Tcherkezian, Director, MSL, Paladin Labs Inc.

“The Canadian Liver Foundation is honoured to support the important work of the CDTRP and, in particular, the research conducted through the annual Innovation Grant. The health and longevity of liver transplant patients is an area of vital importance and one to which the CLF is entirely committed. We welcome the work of all those researchers whose work will be advanced by these grants. May your work truly continue in the CLF tradition of bringing liver research to life.” – Jennifer Nebesky, President and CEO, Canadian Liver Foundation (CLF)

“A project that could mean less biopsies and medication if it works? Yeah! I hate biopsies!” – Addison McArthur, heart transplant recipient, age 9 (for the Addison Fund/TRFBC)

We would also like to thank and acknowledge the hard work of the CDTRP New Initiatives Committee and our volunteer Peer Reviewers for participating in the CDTRP review process and for upholding an excellent level of professionalism and quality.

List of Abstracts

François Martin CarrierUniversité de Montréal, CRCHUM
Effects of intraoperative hemodynamic management on postoperative outcomes in liver transplantation: a multicentre prospective observational cohort study – Theme 2

“Liver transplantation is a life-saving procedure for patients with end-stage liver disease, but it carries a high risk of complications. About 60% of liver transplant recipients suffer from a severe postoperative complication. Few perioperative interventions (conducted just before, during or just after a surgery) have been shown to reduce these complications in liver transplantation. Intraoperative fluid administration and blood pressure management is an important aspect of anesthesia and perioperative care in this population. A restrictive approach to fluid administration has been suggested to improve postoperative outcomes. We propose to conduct a study in Canada to assess the potential effects of fluid administration and blood pressure management on postoperative complications in liver transplantation. Such study will help understand the effects of such intraoperative interventions on important postoperative outcomes for the patients. This study will also inform the design of a future Canadian multicentre perioperative clinical trial in this population and help improve the perioperative care of these very sick patients.”

Cecilia Chaparro, Shannon Wright, and Brooke StewartUniversity Health Network, University of Toronto
MINDFUL: Mental health IN aDults with cystic Fibrosis who Undergo Lung transplant – Theme 5

“Cystic Fibrosis (CF) patients who have a lung transplant often experience emotional distress following surgery. This distress may be described as anxiety, depression or trouble adjusting, and symptoms of this may include low energy, low appetite, feeling sad, worrying more than usual, and problems sleeping. These symptoms can make recovery harder than it needs to be. Currently, there is not a lot of research that studies mental health in CF patients who have had a lung transplant. The goal of our study is to answer the question: What are the mental health needs of CF patients after transplant? We will conduct one-on-one interviews with transplant recipients, their caregivers and healthcare providers who provide transplant follow up care. We will use the information from the interviews in the next phase of research, to develop and test an intervention that meets the mental health needs of the CF lung transplant recipients.”

Jennifer ConwayUniversity of Alberta
Ex Situ Heart Perfusion for Optimization of Pediatric Donor Organ Utilization: Attitudes and Perceptions – Theme 2

“There is a gap between pediatric heart donor organ availability and the actual use of those hearts for pediatric transplantation. This results in a significant percentage of donor hearts which are not utilized. There are a number of reasons for this but long travel times and poor quality of the donor heart are some of the possible reasons. Finding ways to increase the use of pediatric donor hearts can decrease the deaths of children waiting for a transplant. Ex vivo or ex situ organ perfusion (ESHP) is a way to treat and transplant the donor hearts that may allow for longer travel times between donor and recipient sites without the problems that arise with the traditional methods of organ transport. This method has been used in adult heart transplantation but currently there is not a system designed for pediatric donor hearts. Therefore, there is a need for device development to allow the application of ESHP to the pediatric donor hearts. This effort not only requires the development of an appropriate device, but also it is important to gain an understanding of the attitudes and perceptions towards ESHP in the pediatric heart transplantation community as this method for donor organs would be a complete change to what is currently done. This study is therefore designed to assess stakeholder’s attitudes and perceptions of EHSP and to identify barriers to its use in pediatric heart transplantation.”

Esmé DijkeUniversity of Alberta
Into the Unknown: Defining the Optimal Cryopreservation Conditions for Therapeutic Thymic Regulatory T Cells – Themes 4 and 3

“KEEPING IT COOL: FREEZING REGULATORY IMMUNE CELLS FOR CELL THERAPY
Special immune cells called ‘regulatory T cells’ (or ‘Tregs’) are of enormous interest because they naturally suppress harmful immune responses. The use of Tregs as a cellular therapy is being explored by many researchers to treat a variety of immune disorders, including diabetes and transplant rejection. Tregs come from the thymus gland, a structure located in the upper chest. In children having heart operations, the thymus is usually removed because it is in the way of the surgeon. We recently showed that this discarded thymus is a source of huge quantities of very powerful Tregs, demonstrating great potential of Tregs from thymus to be used as a cellular therapy. Ideally, Tregs are collected from the thymus, grown in the laboratory, frozen in a special freezing solution and stored until needed. Freezing cells, however, can result in cell damage and loss. We will study how thymic Tregs are affected by freezing and thawing, and what freezing conditions are best to preserve the Tregs without damage. We will test new ‘anti-freeze’ components that protect Tregs from damage during freezing and thawing. By studying various characteristics of Tregs while they are being grown in the laboratory, we will also try to identify markers that will tell us when it is the best time to freeze the cells during the growth process. Using this knowledge, we can develop an optimal protocol to store thymic Tregs for clinical therapy.”

Lakshman GunaratnamUniversity of Western Ontario
Therapeutic use of recombinant AIM to improve renal transplant outcomes – Themes 3 and 4

“A kidney transplant has the potential to prolong the life of people with kidney failure and immensely improve their quality of life. A major limitation of organ donation is the short lifespan of the organs when transplanted into a person. The damage that happens to an organ during the transplant process (e.g. lack of blood flow to the organ), and then from the person’s immune system (i.e. rejection) are major factors that determine the lifespan of transplanted kidneys. At the molecular level, this damage is caused by dying kidney cells which release their contents into the body and activate an immune response. Our laboratory has discovered a potential therapeutic agent, called “AIM”, which, when given immediately following transplant surgery, can help remove the contents that are released from dying cells and prevent further damage to the transplanted kidney. We now would like to test whether AIM can help prolong the lifespan of transplanted kidneys in an animal model that is similar to human transplantation; where the animals have different genetic backgrounds from each other. We expect that giving AIM to people that receive kidney transplants will reduce the damage caused by transplantation surgery and the effects of the immune response. AIM may become a revolutionary treatment used to make kidney transplants last longer in people with kidney failure.”

Sasan Hosseini-MoghaddamUniversity Health Network, University of Toronto
Mycobacterial Infections in Solid Organ Transplant Recipients (SOTRs) in Ontario from 2002 to 2018 – Themes 5 and 4

“Transplant patients are at risk of infectious diseases because of treatment with medications that suppress their immune system. Nontuberculous mycobacteria (NTM) are bacteria that are normally present in the environment. Inhalation of these bacteria may cause severe illnesses in patients with weakened immune systems. Person-to-person transmission of NTM infection is not common, in contrast to transmission of tuberculosis (TB). Transplant patients with NTM infection and TB may lose their transplanted organs or even die. In this project, we will first use large health databases to identify patients who received organ transplants in Ontario from 2002 to 2018. Then we will identify transplant patients who were infected with TB or NTM by linking to results of laboratory testing done at Public Health Ontario. By comparing rates of infection in transplant patients and the general population, we will determine how much transplantation increases the risk of TB and NTM infections. Next, we will identify transplant patients who died and kidney transplant patients who lost their transplanted kidneys after TB and NTM infection. We will compare these patients with uninfected transplant patients to determine the risk of death after infection in all transplants and the risk of losing transplanted kidneys because of infection after kidney transplant. This information is very important to reduce the risk of TB and NTM infections in transplant patients.

Golnaz Karoubi and Siba HaykalUniversity Health Network, University of Toronto
Repopulation of Long Segment Tracheal Allografts for Transplantation – Themes 3, 4, 5

“Trauma and cancer can lead to injury to long segments of the airway. These patients typically require frequent hospitalization and become dependent on permanent artificial airways. Although tracheal transplantation represents a possible solution for these patients, they would require long-term anti-rejection medication. A novel technique involves using a donor airway, removing all the cells and repopulating it with patient specific cells. The challenge of using patient-specific cells is their limited availability in the airway, and the limited potential for growth. Our study focuses on using a novel cell population; a stem cell population that can be easily procured from recipients through simple techniques such as skin biopsies. The cells have the unlimited ability grow and of becoming airway specific cells. The goal of this project is to evaluate these cells in a preclinical model. This stem cell population will be seeded on long segment airway defects in a bioreactor that has been used in our laboratory for several years. Following which, they will be transplanted in a survival model. This represents the first step in creating long segment airway scaffolds which can be transplanted without the need for anti-rejection medication.”

Caroline LamarcheUniversité de Montréal
BK-specific T-cell immunotherapy; moving towards a clinical trial – Themes 4, 3, 5

“Solid organ transplantation was made possible by the use of immunosuppressive drugs to control the immune system which sees the organ as foreign and naturally would reject it. BK polyomavirus is usually an inoffensive virus that stays and hide in kidneys, controlled by our immune system. However, because of the weaker immune system of kidney transplant recipients (KTR), it can reactivate in the graft and lead to a decrease in graft function and even graft loss. For now, the only treatment is to decrease the amount of immunosuppressive drugs, but it comes with the risk of graft rejection. Our ultimate goal is to develop a new method to give back the ability to fight and control this virus without increasing rejection’s risk, using the patient’s own immune system. We want to collect immune cells (white blood cells) from the blood of patients affected by this virus and expand the cells that are specifically able to control it in the lab (in vitro). The long term objective of this project is to devise a treatment that would involve the re-injection of the patient’s own immune cells, but that are now able to stop this virus. This approach has been used mainly in bone marrow recipients and was proven to be very effective. However, is has never been tested using a KTR own immune system. We previously showed that we are able to collect and expand those cells from KTRs affected by this virus in the lab. Those cells were shown to be safe for the graft and effective against the virus. We propose here to set the foundation to move to the first clinical trial by fulfilling the data needed in order for Health Canada to approve our study. We also want to study which of the most commonly used immunosuppressive drugs have more impact on the cells trained to fight this virus. This will allow us to apply for a pan-Canadian clinical trial as well as helping us deciding which of the immunosuppressive drugs should be decreased first in the case of BK polyomavirus reactivation.”

Megan LevingsUniversity of British Columbia, BC Children’s Hospital Research Institute
Development and validation of a novel assay to quantify alloantigen specific T cells – Themes 4, 1, 2, 5

“Following transplantation, immune cells in the recipient recognize the new organ as a foreign invader and subsequently launch an attack to destroy it. To stop this immune response, transplant recipients are placed on immunosuppressing drugs that severely reduce the immune system’s normal ability to fight off infections and cancers. It is therefore critical to prescribe just enough immunosuppressing drugs to prevent organ rejection, but not so much that patients suffer from the numerous side effects of these medications. Currently, there are no tools available to measure how well immunosuppression is working in each patient. Although biopsies are often performed to assess whether rejection is happening or not, they are often done too late, after immune cells have caused irreversible organ damage. We need a way to measure immune responses to transplants so that changes in immunosuppression can be made proactively, rather than reactively. We propose to develop a new test that will rapidly measure immune responses to an organ using a small amount of blood. The test is based on a fascinating immunological phenomenon whereby immune cells from the recipient that want to kill the transplanted cells pick up proteins that are exclusively expressed on the very cells they are trying to attack, allowing us to quantify the number of these killer immune cells. We believe that by quantifying these dangerous immune cells, we will be able to determine the risk of transplant rejection and give clinicians the information they need to prevent rejection and individualize immunosuppressive drug regimens.”

Bruce McManusUniversity of British Columbia
Identification of novel cell-specific immunosuppressive therapies from high resolution single-cell RNA sequencing – Theme 4

“Transplantation is the standard of care for millions of patients with end stage heart failure. Unfortunately, acute immunological rejection of the transplanted heart and the prolonged use of immunosuppressants to combat this rejection that have many toxic side effects continue to pose major issues for long term patient outcomes. Methods to identify novel drug candidates in an expedited manner and new drugs that can be delivered more precisely to the site of rejection remain major unmet needs for in heart transplantation research and clinical care. Our hypothesis is that high resolution molecular profiling and machine learning approaches can precisely identify new molecular pathway candidates that can be targeted to treat acute rejection and organ damage. Our current data suggest that there are specific sets of molecules and immune cells that are significantly altered in the heart tissue and blood during acute rejection. In this project, we will perform single cell RNA sequencing on heart biopsy tissue from transplant patients to better delineate the molecular changes in immune cells during acute rejection. We will then use this data and large-scale drug databases to computationally identify drug targets and drug combinations that can reverse the molecular changes. Our team is comprised of pioneers in cardiovascular pathology, diagnostics development, and bioinformatics. This work can lead to a better understand of acute rejection at a single-cell level, and future projects where we can use specific drug delivery technologies to bring novel treatments to immune cells with high efficacy and low toxicities.”

Vicky NgThe Hospital for Sick Children, University of Toronto
Long-Term Outcomes and Health Status of Pediatric Liver Transplant Recipients Off Immunosuppression – Report from a North American Multi Center Registry – Theme 5

“Current standard of care following liver transplantation includes life-long maintenance anti-rejection medicine, which is individually tailored with the goal of keeping the transplanted organ healthy while avoiding complications caused by the medicines themselves. There are also risks of “too little” immunosuppression, and so best outcomes mandate balancing the needs of the patient and the transplanted organ. This study seeks to learn from children who have achieved the goal of transplant medicine: a healthy liver without anti-rejection medicine. Many of these children are concurrently followed in the SPLIT registry, which houses the largest longitudinal database on children transplanted in Canada and the United States. This study provides the opportunity for us to characterize the clinical outcomes and health status of children off and on immunosuppression enrolled in a multi-center longitudinal database, and include assessment of the risk vs. benefit of being able to stop anti-rejection medicines while maintaining the health of both the patient and of the transplanted liver.”

Vicky Ng and Binita KamathThe Hospital for Sick Children, University of Toronto
A Novel Ultrasound-based Tool to Assess Muscle Mass in Children With and Without Liver Disease – A Pilot Feasibility Study – Theme 5

“Muscle loss (a concept called sarcopenia) is associated with poor outcomes (such as longer intensive care unit stays, prolonged hospital stays, and increased serious infections) following liver transplantation. Computed tomography (CT) imaging of a muscle in the abdomen (called the psoas muscle) is the recommended best technique to diagnose sarcopenia in patients with end-stage liver disease. However, CT is not an ideal tool to serially monitor muscle loss in children because of radiation risks. In adults, ultrasound is used to quickly and safely measure thigh muscle thickness (without risks of radiation exposure) in order to monitor muscle loss. Our study proposes to assess the feasibility of measuring thigh muscle thickness in babies and young children using ultrasound. We believe that the importance of assessing and serially monitoring sarcopenia with a safe and readily available tool such as ultrasound in children is that we will be able to identify muscle wasting prior to transplantation, and then offer targeted interventions to these patients in order to improve their outcomes after liver transplantation.”

Ian RogersUniversity Health Network
Building Matched Organs using Patient-derived Stem Cells – Theme 3

“In Canada, 2.6 million people have kidney disease. The most effective therapeutic strategy for kidney failure is dialysis or transplantation. However, the average waiting time for a donor kidney is 5-8 years and the dialysis survival rate is 33% at 5yr. This underscores the need for the development of new methods for treating kidney disease. Current kidney therapy relies on medication, dialysis and transplantation. Cell therapies, whereby disassociated cells are introduced to the area of damage, are not efficient due to the density and complexity of the kidney and result in very few cells actually engrafting. This means improved treatments will come from drug discovery, and for patients with chronic and severe kidney disease, transplantation. Therefore, transplantation will remain as a common treatment procedure for end stage renal disease. Thus the demand for donor organs will continue to increase and organ shortage will be the major hurdle to treating patients. To increase the donor pool, more marginal kidneys are used resulting in increased delayed graft function with a negative impact on the patient’s long-term outcome. In contrast, building customized kidneys with recipient generated stem cells would generate an unlimited supply of high quality tolerant grafts without the need for immunosuppression. Kidney disease is an ideal model for personalized organs because patients can be maintained on dialysis while the organ is being manufactured. There is a strong precedent established in the literature for rebuilding organs such as the liver, lung and heart.”

Dmitry RozenbergUniversity Health Network, University of Toronto
Feasibility of a Home-Based Exercise Program in Liver and Lung Transplant Recipients for Management of Post-Transplant Metabolic Syndrome: A Pilot Randomized Controlled Trial – Theme 5

“Background: Liver (OTL) and lung transplant (LTx) recipients are at risk for post-transplant metabolic syndrome (PTMS), a condition of excess body weight, elevated blood sugar, cholesterol and blood pressure. PTMS is common affecting 50% of OTL and 25% of LTx recipients in the late (> 1-year) post-transplant period and associated with increased cardiovascular illness and long-term survival. There is some evidence that supervised exercise can improve individual elements of PTMS in the early post-transplant period. However, it remains unclear whether a home exercise program can be performed with good adherence and training intensity. Thus, a pilot study is needed before this can be performed in a large clinical trial to assess effects on PTMS. Objectives: 1) To study whether a three-month home exercise program in OTL and LTx recipients can be successfully performed by participants at one-year post-transplant with sufficient adherence. 2) To estimate the effect of exercise training on PTMS, body make-up, self-confidence with exercise and quality of life. Methods: We will randomly assign 20 OTL and 20 LTx patients at one-year post transplant to receive a homebased exercise program versus usual care. The exercise group will perform walking and muscle strengthening exercises over a 12-week period guided by a trainer through weekly phone calls and digital application with manuals, videos, and several strategies to improve self-confidence with exercise. Both groups will receive advise at the start on healthy eating and physical activity. Program satisfaction and adherence will be evaluated and estimates of the effects of exercise on PTMS, body make-up, walking ability, and quality of life will be assessed. Significance: This study will be the first of its kind to assess whether home exercises can be achieved with a good enough training adherence using health technology and strategies to promote self-confidence with exercise. The results will help us with designing future studies to offset the effects associated with PTMS.”

Nazia SelznerUniversity Health Network, University of Toronto
Prevalence and Incidence of liver disease and access to liver transplant and living liver donation in ethno-racial communities (ACCESS-LT) – Theme 1

“The incidence and prevalence of liver cirrhosis and liver cancer are rising in Canada. Liver transplantation is a life-saving treatment for many of these patients. However, members of immigrant and ethnic and racial minority communities in Canada face myriad barriers. Many patients do not know they have liver disease and are not receiving timely diagnosis or referrals to a transplant centre. In some communities, there is low awareness and support for organ donation, whether deceased or living. The goal of ACCESS LT project is to study the epidemiology of liver disease and access to liver transplantation in ethno-racial communities in Ontario and in Canada and engage patients, donors and community leaders to address barriers to transplantation. This project will ensure that One-Transplant- For-Life by fulfilling every donor opportunity and turning transplantation into a cure, the transplant community must expand and diversify the pool of available organ donors to better match the needs of those with organ failure.”

Scott TebbuttUniversity of British Columbia
Investigating regulatory T cell gene signature in blood during acute cardiac transplant rejection – Themes 4, 5

“Patients receive heart transplants as a life-saving measure after heart failure; thus, ensuring the success of the transplant is of utmost importance. Rejection is a primary cause for heart transplant failure, and consequently, patients must take drugs that suppress the immune system to prevent rejection. However, these drugs are highly unspecific and cause serious side effects that can be life-threatening. New immunosuppressive drugs that can prevent transplant rejection while allowing normal immune function can greatly improve care and patient outcomes. One type of immune cells called regulatory T cells (Tregs) can effectively suppress the immune system in a highly specific manner. We believe these cells can be effective in preventing and treating acute rejection. Working toward such a goal, our research plan is to first understand how Tregs behave during rejection. We will track their activities by measuring 46 genes in the blood of heart transplant patients throughout the first year post-operation. These genes provide valuable information on the risk of acute rejection at a given time and on changing Treg responses. This work will help us understand the role that Tregs play during rejection and can lead to creating novel therapies for preventing and treating rejection for heart transplant patients.”

Suzanne VercauterenUniversity of British Columbia
Evaluating the Heterogeneity of T Cell Phenotypes in Pediatric Renal Transplant Recipients: Associations with Patient and Transplant Factors, and Alloimmune Activity – Theme 5

“Some children with a kidney transplant experience rejection, which can result in reduced kidney function or even loss of their transplant. Children are at a higher risk than adults for losing their kidney transplant function. Knowing which children are at higher risk would help identify who may benefit from new treatments. We are still looking for a better test to tell us who may be at of kidney rejection. We know that the balance between two types of white blood cells may be important: effector T cells (attack foreign cells), and regulatory T cells (help the immune system accept foreign cells). Finding higher levels of the regulatory T cells (compared to effector T cells) in the blood may help us to predict who is likely to accept the kidney transplant long term. For children with lower levels, there might be options for different treatments to improve these changes. We will study the levels of different T cells in the blood of patients with and without kidney rejection along with other markers of the immune response in the urine to see if this would help us predict rejection. Our hope is to start using this kind of approach both in the clinic to monitor how children are doing with their transplant, and also for research to develop better treatments for rejection.”

Darren YuenUniversity of Toronto
Nanobubbles: a new way to non-invasively measure donor kidney ischemia-reperfusion injury – Theme 3

“While kidney transplantation can be a “gift of life”, we know that kidneys are injured during the transplant surgery, and that this injury can affect kidney function. This damage is due to the loss of blood flow when a kidney is taken out from the donor (“ischemia”) and put into a recipient (“reperfusion”). This process, called “ischemia-reperfusion injury” (IRI), occurs in every transplanted kidney. A major feature of IRI is blood vessel damage, resulting in less blood flow in the kidney after it is transplanted, and leaky blood vessels that allow fluid to inappropriately accumulate in the kidney. IRI severity determines how well the kidney will work after transplant. Doctors have no way of measuring IRI severity, and so can not easily predict how well a kidney will work. Thus, doctors can not tell patients what to expect after transplantation, and scientists can not easily test new anti-IRI drugs. We have developed a new ultrasound technique that measures kidney blood vessel damage. This technique can be done quickly, and based on our preliminary experiments seems to measure IRI in the kidney. We want to test if our new technique can accurately measure kidney IRI severity, and predict how well the kidney will function after IRI. These initial experiments will be done in mice, but if successful, will lead to studies in large animals and then a first-in-human clinical trial. Our hope is to provide a new tool for doctors to help better manage kidney IRI, and thus improve transplant outcomes.”