In 2009, PSC Partners Seeking a Cure awarded its first set of research grants. For PSC Partners, this was a milestone, an important step towards taking us closer to new treatments and an eventual cure. PSC Partners Canada joined the grants program in 2016. Since the inception of the program, together, over USD $5,000,000 has been allocated to promising PSC research projects (as of Dec 2021). The Canadian affiliate grants made currently total CAD $770,000.
We thank our Canadian donors who have supported our mission to drive research to identify treatments and a cure for primary sclerosing cholangitis (PSC), while providing education and support for those impacted by this rare disease. Your contributions have made these research awards possible.
To see a record of all research funded by both US-based PSC Partners Seeking a Cure and PSC Partners Canada, please visit here.
Grants 2016 to 2021
Research awards funded by PSC Partners Canada in reverse chronological order.
- Research Grant: Closing the Gap: Machine Learning Evaluation of Liver Transplant Wait-List Prioritisation for Patients with Primary Sclerosing Cholangitis PI: Mamatha Bhat, MD, PhD, University Health Network, Co-PIs: Wei Xu, PhD and Gideon Hirschfield, MB, BChir, FRCP, PhD Summary: Primary sclerosing cholangitis (PSC) is a chronic liver disease that can result in cirrhosis and complications compromising survival. There is no proven treatment for this disease and many patients finally require liver transplantation as their disease progresses to end-stage liver disease. However, PSC patients are particularly disadvantaged by the current organ allocation system, as their degree of illness is not accurately reflected by the scoring system for priority on the waiting list. This is an urgent problem in need of rectification to save lives of PSC patients. Therefore, we aim to describe the current condition and challenges faced by individuals with PSC who are referred and listed for transplantation. Then, we aim to design a more effective prioritization system using artificial intelligence tools on dynamic changes in clinical and laboratory information from PSC patients to provide them with the best possible chance of getting transplanted.
- Research Grant: Unfolded Protein Response (UPR)-based therapies in a mouse model of PSC PI Richard M. Green, MD, Northwestern University Feinberg School of Medicine Summary: There are currently no effective treatments for patients with Primary Sclerosing Cholangitis that slow liver disease progression or prevent the development of liver cancer. We have determined that a protective signaling mechanism in the liver termed the unfolded protein response (UPR) is important in the progression of PSC and other cholestatic liver disease. Abnormalities of two of these UPR proteins termed XBP1 and CHOP appear to be particularly important in PSC and in causing cholestatic liver injury. In this proposal, we use a mouse model of PSC termed the MDR2-knockout mouse to determine the effectiveness of a novel drug that increases XBP1 in the liver, and a genetic therapy that reduces CHOP in the liver. Both of these effects should slow or prevent liver disease progression of the PSC mice and may help determine their potential as future therapies for PSC patients. This pre-clinical therapeutic study will be essential for the further development of these therapies prior to testing them in patients with Primary Sclerosing Cholangitis.
- CASL PSC Partners Seeking a Cure Canada Award to Dr. Bellal Jubran for the best abstract on PSC presented at Canadian Liver Meeting: Hepatolithiasis Is A Frequent And Prognostic Finding In Patients With Primary Sclerosing Cholangitis, B. Jubran, M. Ismail, M. Stein, D. Little, B. Hansen, A. Gulamhusein, G. Hirschfield (Awarded through Canadian Association for the Study of Liver Disease)
- Research Grant: Exploring the metabolic profile of T cells in patients with PSC Evaggelia Liaskou, PhD, University of Birmingham Summary: We and others have shown that a type of immune cells called T cells, play a key role in PSC and they are normally found in close proximity to the bile ducts. T cells rely on nutrients which they take up from their environment to maintain their function and survival. In many diseases, immune cells become overactivated and start to function abnormally by releasing proteins to their environment. We think this is also happening in the setting of PSC, therefore, we aim to study: 1) how do T cells control their nutrient intake from the environment and 2) whether damaged bile ducts affect how T cells behave. Through this project we hope to understand the disease better and discover new approaches to treat PSC by changing how T cells behave.
- Research Grant: Creation of liver organoids from pluripotent stem cells derived from donors with PSC Alan C. Mullen MD, PhD and Daniel S. Pratt, MD, Harvard Medical School Summary: PSC is a disease that leads to bile duct injury and liver fibrosis. Progression of this injury frequently results in liver failure and is associated with an increased risk of cancer. There are currently no effective therapies other than liver transplantation. There remains an urgent need to understand how PSC develops so that we can find approaches to inhibit the progression of liver disease. First degree relatives of patients with PSC have ~100 fold increased risk of developing PSC compared to the general population. This finding and the work of groups linking specific genes to an increased risk of PSC strongly suggest that there is an inherited or genetic risk for PSC. Our proposal will advance our understanding of how genetics, or the sequence of DNA in patients with PSC, affects the development of the liver and the interaction between different cell types in the liver. To answer these questions, we propose to develop pluripotent cell lines from donors with PSC and from healthy controls and then direct these cells to differentiate into miniature livers in culture. Pluripotent stem cell lines can be differentiated into nearly any cell type in the body, and we now have approaches that allow us to convert blood cells into these pluripotent cells. We can then direct these pluripotent cells to differentiate into small clusters of cells that contain the cell types that make up the liver, which are called liver organoids. By analyzing the genes expressed in the different liver cell types and how these different cell types interact with each other in organoids, we can begin to understand how the sequence of DNA in patients with PSC puts them at risk of developing liver failure and cancer. This project is the first step in developing pluripotent stem cell lines and differentiating them into liver organoids and will form the foundation for future work to expand our understanding of how genetics affects development of PSC and the risk of liver cancer.
- Research Grant: Mucosal markers to predict the onset of colonic neoplasia in inflammatory bowel disease patients with PSC Joel Pekow, MD, University of Chicago Summary: Patients with inflammatory bowel disease (IBD) who have a diagnosis of primary sclerosing cholangitis (PSC) carry a significant risk of developing colon cancer. Although the phenotype of colon cancer in PSC patients differs from IBD patients without PSC, little is known regarding mechanisms or predictors of cancer development in these high-risk patients. In preliminary studies, we demonstrate that PSC patients with IBD can be classified into 3 groups based on gene expression profiles from the proximal colon. One of these groups carries a higher risk of colon dysplasia and has enrichment of genes associated with increased mucosal plasma cell expression. The goal of this proposal is to investigate if plasma cell numbers and genes associated with plasma cell expression can be used to predict neoplasia in patients with PSC. For these studies, we will utilize a prospectively followed cohort of patients with PSC for which we have collected extensive biosamples and clinical metadata. We anticipate that these studies will provide novel markers for colon cancer development in patients with PSC as well as expand our understanding of mechanisms of cancer and inflammation in this population.
- PSC Partners Canada Fellowship in PSC and Autoimmune Liver Disease: a clinical and research fellowship in primary sclerosing cholangitis (PSC) for a period of one year at the direction of Dr. Aliya Gulamhusein and Dr. Gideon Hirschfield in the Toronto Centre for Liver Disease at University Hospital Network (Toronto Centre for Liver Disease) (award matched for a 2nd year by Toronto General and Western Hospital Foundation)
- CASL PSC Partners Seeking a Cure Canada Award to Dr. Julian Hercon for the best abstract on PSC presented at Canadian Liver Meeting: Evolution of autoimmune cholangitis and primary sclerosing cholangitis in a pediatric cohort. J. Hercun, P. Willems, F. Alvarez (Awarded through Canadian Association for the Study of Liver Disease)
- PSC Partners Canada Research Fellowship in primary sclerosing cholangitis (PSC) for a period of one year at the direction of Dr. Sonya MacParland in the Soham & Shaila Ajmera Family Transplant Centre at University Hospital Network. The fellow to focus on basic research to identify cellular mediators of PSC pathogenesis and targetable immunological defects that underlie the progression of PSC. (Award matched for a 2nd year by Toronto General and Western Hospital Foundation)
- Nov 2021 Publication: Single-Cell, Single-Nucleus, and Spatial RNA Sequencing of the Human Liver Identifies Cholangiocyte and Mesenchymal Heterogeneity (Open Access)
- PHENOTYPES OF PATIENTS WITH RECURRENT PSC AFTER LIVER TRANSPLANTATION: AN INTERNATIONAL NETWORK STUDY Aliya Gulamhusein, MD, MPH, FRCPC, Assistant Professor, University of Toronto, Clinical Investigator, Toronto General Hospital, Toronto Centre for Liver Disease, Toronto, Ontario, Canada, Amount Awarded: USD $80,000 over two years, Project Summary: Recurrent PSC (rPSC) is a distressing complication that occurs in some PSC patients post liver transplantation and is associated with a four-fold increased risk of graft failure or death. This research is directed at developing an improved understanding of clinical and immunopathogenic pathways underpinning recurrent PSC. We aim to comprehensively characterize (phenotype) a prospective cohort of patients with PSC post liver transplant and use newly emergent mass cytometry technology to understand clinical, serologic, microbiological, and immunologic changes associated with development of rPSC. In addition, we will establish an international network among liver transplant centers worldwide to characterize clinical risk factors associated with rPSC. Results of this research will improve understanding of disease pathogenesis, and may also illuminate “immune signatures” associated with outcomes and thus has potential to identify targets for therapy. This disease is devastating to patients and their families, is costly to the health care system, and is a critical unmet need. Identifying clear risk factors for rPSC requires a systematic and comprehensive phenotypic evaluation of patients to identify those in greatest need of targeted early intervention.
- INTEGRIN AVB6 AS A THERAPEUTIC TARGET FOR PRIMARY SCLEROSING CHOLANGITIS – ASSOCIATED CHOLANGIOCARCINOMA Yury V. Popov, MD, PhD, Director, Liver Fibrosis Research, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, Amount Awarded: USD $60,000 over two years. Project Summary: Cholangiocarcinoma (CCA) is a liver and bile duct cancer of unknown cause and rising incidence worldwide. CCA is a devastating complication of PSC, difficult to diagnose and associated with high mortality. Treatment options are extremely limited as PSC-associated CCA patients often do not qualify for liver transplantation. In the absence of drug options in the treatment of PSC-associated CCA, poor prognosis and high mortality, new therapeutic approaches are urgently needed. Integrin αvβ6 is an epithelial tissue cell surface receptor which is virtually absent from normal livers. It has been shown to be markedly upregulated on activated bile duct epithelial cells and liver cells with features of ductular transformation, correlating with fibrosis stage, both in rodent models of fibrosis and in patients with chronic liver disease. Integrin αvβ6 binds and activates transforming growth factor beta and is expressed on liver progenitor cells that are linked to both biliary fibrosis and the formation of cancer. This study proposes to develop a model of CCA in a mouse model of PSC (mdr2-/- ) and to assess the impact of integrin αvβ6 on the development of CCA and possible therapeutic potential of drugs targeting this pathway. Since several αvβ6-specific inhibitors are currently at various stages of drug development for other indications, rapid translation of findings into clinical practice is feasible. Completed Study (2019) Update: In the first year, a new mouse model of cholangiocarcinoma (CCA) was established on PSC-like Mdr2-/- background, termed SB CCA.Mdr2-/- model. Susceptibility to CCA in this system is driven by the biliary injury and fibrosis in Mdr2-/- mice, recapitulating the predisposition to biliary cancer in human PSC. Most of CCAs arising in SB CCA.Mdr2-/- mice express various levels of αvβ6 integrin. In the second year, we refined the model characterization by replication (and thus increasing the samples size to at least 9 mice/group), and performing long-term survival analysis and interrogated the influence of common laboratory mouse genetic backgrounds (FVB, C57Bl/6, BALB/c) on CCA susceptibility and growth. These tests confirmed 1) model reproducibility, 2) major differences in tumorigenesis observed between healthy and fibrotic hosts, and 3) established the surrogate and hard end-points for future therapeutic efficacy tests. Further, we utilized T- and B- cell deficient Mdr2-/-;Rag1-/- double-mutants to demonstrate that adaptive immunity functionally restricts CCA growth, suggesting that our model is suitable for testing novel immunotherapies. Ongoing experiments interrogate the role of αvβ6 and related integrins as a potential therapeutic target in PSC-associated CCA using genetic and pharmacologic approaches in the SB CCA.Mdr2-/- model. We are preparing manuscript describing the model and develop several grant applications, both NIH and industry-sponsored, that directly stem from research supported by this grant. April 2020 – Publication: A novel non‐bile acid FXR agonist EDP‐305 potently suppresses liver injury and fibrosis without worsening of ductular reaction “Conclusions: EDP‐305 potently improved pre‐established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP‐305 in fibrotic liver diseases including cholangiopathies and NASH.”
- THE ENTEROHEPATIC METABOLOME IN PRIMARY SCLEROSING CHOLANGITIS Steven P. O’Hara, PhD, Assistant Professor of Medicine and Biochemistry/Molecular Biology, Mayo Clinic, Rochester, MN, USA Amount Awarded: USD$60,000 over two years. Project Summary: Emerging data, including work from our laboratory and clinical research group, suggest fundamental disease associated mechanisms in primary sclerosing cholangitis (PSC) that are centered on molecules derived in the gut and brought to the liver through portal circulation (gut-liver axis). The gut-liver axis has been proposed to play a significant role in the initiation, progression, and adverse clinical events associated with PSC; however, this has not been directly tested to date. Our goal is to determine whether there are differences in the metabolites (proteins, fats, and other chemicals) in the portal vein (which delivers blood from the intestines to the liver) and in bile between individuals with primary sclerosing cholangitis and those without PSC. We anticipate that patients with PSC will have distinct alterations in the portal venous and bile metabolites compared to controls; and these alterations may be amenable to future therapies.