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 initiated the Canadian the grants program in 2016. Over C$900,000 has been allocated to research from the Canadian affiliate.

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.

Grantees through 2022

Grants 2016 to 2024

Research awards funded by PSC Partners Canada in reverse chronological order.

2024

  • Molecular Mechanisms Regulating Neutrophil-Induced Oxidative Stress in Primary Sclerosing Cholangitis (PSC). Principal Investigator: Nidhi Jalan-Sakrikar, Ph.D., Mayo Clinic. AWARD: $60,000 over two years Project Summary: Persistent inflammation in PSC can lead to liver damage through scarring that leads to fibrosis and cirrhosis. Neutrophils are the most abundant white blood cells in humans and have been well established as first responders to acute inflammation. Under normal conditions, neutrophils contribute to tissue repair and inflammation resolution. However, in chronic diseases, infiltrated neutrophils are exposed to inflammatory conditions in the tissue that impacts their properties which can lead to reduced pro-resolving function thereby causing tissue damage. Bile duct cells isolated from PSC patients had increased number of associated neutrophils compared to those from non-PSC control patients. In this project, we aim to investigate the mechanism responsible for the observed neutrophil infiltration. We also plan to examine the impact of the infiltrated neutrophils on the bile duct cells and how the association with bile duct cells can influence changes in neutrophils. Furthermore, in our preclinical animal models of PSC we will employ pharmacological inhibitor and neutralizing antibody approach thereby interfering with neutrophil infiltration to investigate its therapeutic potential in reducing chronic liver inflammation and fibrosis.
  • CASL PSC Partners Seeking a Cure Canada Award  to Audrey-Anne Laovoi of University Laval for the best abstract on PSC presented at the Canadian Liver Meeting: Protectin DX improves the response to obeticholic acid in liver cells. Authors: A.A. Lavoie, M. Verreault, J. Trottier, R. Maltais, J.Y. Sancéau, D. Poirier, A. Marette, O. Barbier.
  • PSC Partners Canada Research Funding: to support a graduate student or postdoctoral researcher in PSC and Autoimmune Liver Disease; three-year funding to support research in primary sclerosing cholangitis (PSC) and autoimmune liver disease for a period of three years, supervised by Dr. Gideon Hirschfield with collaboration Dr. Bettina Hansen at University Hospital Network (Toronto Centre for Liver Disease) (award matched by UHN Foundation)

2022

  • Targeting PSC Pathogenesis Using a Bifunctional Peptide, GP119, in the Mdr2-/- Mouse Model of PSC and Novel Multicellular Human-Derived 3D PSC Organoids. PI: Heather Francis, PhD, FAASLD, Indiana University Co-PI: Gianfranco Alpini, PhD Summary: PSC is characterized by ductular reaction (expansion of bile ducts), inflammation and liver fibrosis. There are several models used to study PSC including animal models (Mdr2-/- mice) and liver organoids. Developing drugs for human use is critical to offer relief from the debilitating symptoms and PSC disease progression. The GP119 drug is approved for phase 1 clinical studies by Canada Health and our studies in both the mouse model of PSC and in human PSC-derived organoids will support the use of GP119 in a potential phase 2 clinical trial in PSC patients. The experiments proposed using human-derived 3D organoids will also allow us to examine the effects of GP119 in a liver microenvironment with potential for personalized medicine applicability. UPDATE: Jan 2024: Summary of progress: Over the past year we have demonstrated in both the mouse model of cholestatic liver injury and in human PSC-derived organoids demonstrate that usage of GP119 reduces PSC phenotypes/characteristics such as ductular reaction (increased cholangiocyte reactivity) and hepatic tissue fibrosis. These preliminary findings are exciting and we will continue to confirm by evaluating PSC characteristics in Mdr2-/- mice treated with GP119 along with liver organoids comprised of cells from explanted livers (control and PSC). Dr. Alpini retired during September of 2023; however, we are continuing these studies in collaboration with the transplant surgeon, Dr. Burcin Ekser and have made significant progress. All animals have been treated with GP119 and we will continue to evaluate the characteristics of PSC and continue with our liver organoid studies.
  • CASL PSC Partners Seeking a Cure Canada Award  to M. Ismail for the best abstract on PSC presented at Canadian Liver Meeting: LONGITUDINAL STABILITY OF DISEASE ACTIVITY IN PRIMARY SCLEROSING CHOLANGITIS: A TREATMENT TARGET FOR NEW THERAPIES? Authors: M. Ismail, A. Gulamhusein, M. Cunningham, C. Plaginnakos, G. Hirschfield, B. Hansen, TCLD, UNIVERSITY OF TORONTO, Toronto, Canada

2021

  • 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. Update 2023: Methods: We retrospectively reviewed waitlist outcomes of 4,666 and 144 PSC patients from the Scientific Registry of Transplant Recipients (SRTR) and University Health Network (UHN) datasets respectively. We subsequently built three machine learning algorithms from the SRTR to predict waitlist outcomes using time dependent c-index. We then identified the best performing model, and introduced PSC-specific variables to assess their impact on the model. We compared our models with MELD-Na and MELD 3.0. Results: Three machine learning algorithms were developed: Cox Proportional Hazard (CPH), Random Survival Forest (RSF) and DeepSurv. RSF was the best performing and subsequently fine-tuned using disease specific variables. The c-index for MELD 3.0 was below 0.7 at 1 month, 6 months and 1 year on waitlist when tested on UHN patients. The average c-index increase to above 0.9 with the introduction of PSC-specific variables trained and tested on UHN patients. Conclusion and Relevance: Advanced machine learning models using PSC-specific clinical factors can outperform the MELD-Na score for prediction of waitlist mortality and dropout. Risk stratification tools that better account for disease specific factors have the potential to be adopted more broadly as application of advanced informatics in clinical practice grows. Related Publications: Onofrio F, Zheng K, Xu C, Chen S, Xu W, Vyas M, Bingham K, Patel K, Lilly L, Cattral M, Selzner N, Jaeckel E, Tsien C, Gulamhusein A, Hirschfield GM, Bhat M. Living donor liver transplantation can address disparities in transplant access for patients with primary sclerosing cholangitis. Hepatol Commun. 2023 Aug 3;7(8):e0219. doi: 10.1097/HC9.0000000000000219. PMID: 37534935; PMCID: PMC10552969.,
  • 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)

2020

  • 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. Year 2 Update: We successfully generated iPSCs from two donors with PSC and two controls matched by sex and age (within 5 years) and then differentiated each iPSC line into liver organoids. We also tested how these organoids responded to different bile acids to identify the conditions that induced the most inflammatory changes. With successful generation of iPSCs and differentiation into liver organoids, we will now be able to perform single cell RNA sequencing and histological analysis of liver organoids from these donors under control and injury conditions to investigate how genetic changes in PSC affect cholangiocyte-cholangiocyte interactions and the interface between cholangiocytes and neighboring cell types in the liver. These studies have served as a proof of concept to demonstrate that liver organoids can be produced efficiently from induced pluripotent stem cells from PSC patients. Further analyses may also generate hypotheses to explain how genetic changes in PSC affect gene expression and cell-cell interactions.
  • 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. Update Year 2: Funding from PSC Partners Canada has enabled our group to improve understanding of risk factors and biologic mediators of colon cancer in patients with IBD and PSC. The funding has contributed to advancement in three main areas: 1. Ongoing recruitment for a biobank of PSC-IBD patients, 2. A clinical study examining risk factors for colon neoplasia in patients with IBD and PSC, and 3. A translational study examining gene expression in the colon of patients with IBD-PSC and the impact of gene expression on risk of developing colorectal neoplasia. During the grant period, we have continued to recruit and consent patients in a large database and biospecimen repository of IBD patients with PSC. To date, we have recruited over 100 patients with PSC that are closely matched with IBD patients without PSC and healthy controls. Patients have been followed for up to 8 years with collection of blood, colonic biopsies, and stool. This resource has enabled us to complete these studies and will facilitate research into mechanisms and outcomes in patients with PSC in the future. We performed a study examining risk factors for colon neoplasia in patients with PSC. We identified patients with PSC and IBD who did not have a history of neoplasia and had more than one colonoscopy at our institution. Patients with greater inflammation of the lining of the colon by visual and microscopic appearance in the right colon over time had a greater risk of developing colon neoplasia. These findings support a practice of regular assessment of inflammatory activity in patients with IBD and PSC and may lead to changes in goals of IBD treatment in IBD-PSC patients. We also conducted several analyses examining expression of genes in the colon of patients with IBD-PSC, IBD without PSC, and healthy controls. Patients can be divided into one of four groups, based on if their individual gene expression is similar to other patients in a given group. Patients with PSC who fall in one of these groups are more likely to have neoplasia in the colon and more likely to develop neoplasia in the future. These findings improve our understanding of why neoplasia develops in IBD with PSC and may lead to clinical biomarkers used to predict neoplasia in IBD patients with PSC. Two manuscripts have been prepared using the data above, submitted for publication, and are currently (as of 9/2022) undergoing revisions.
  • 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. 
  • 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)

2019

  • 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)

2018:

  • 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.

2017

  • 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.”

2016

  • 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.