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UHN has announced a drug discovery partnership with Providence Therapeutics, a leading Canadian biopharmaceutical company developing messenger RNA (mRNA) vaccines and therapeutics.
UHN and Providence will partner to develop novel mRNA-based vaccines and therapeutics for those living with difficult to treat cancers and infectious diseases. The partnership will draw on UHN’s renowned clinical research and discovery capabilities, as well as Providence’s proprietary, clinically validated mRNA platform technology, with commercialization efforts led by Commercialization at UHN. The product development and subsequent manufacturing will be done in Canada, thereby directly benefiting Canadian patients.
This collaboration will also help position Ontario as a major hub for the development of new mRNA-based therapeutics. Programs developed through this partnership aim to produce affordable medicines for Canadians.
“Our partnership with Providence demonstrates the strength of discovery research at the University Health Network and our potential to fuel innovative therapeutic options for patients, addressing some of today’s top health concerns,” says Brad Wouters, Executive Vice President, Science and Research, UHN. “This partnership will help us get homegrown treatments to patients faster and is a key path forward for research discoveries to evolve into new medical therapies.”
“This partnership will allow us to continue to develop immunotherapy as a breakthrough strategy in cancer treatment and paves the way for new therapeutic options for other diseases,” says Pamela Ohashi, Director, Tumor Immunotherapy Program, Princess Margaret Cancer Centre, UHN. “mRNA technology is a novel and powerful tool to improve cancer therapies and we expect to be able to test initial impact of new therapeutic options in clinical trials as early as next year.”
“The launch of this collaboration marks an important milestone for our company, as we work with the top research hospital network in Canada to demonstrate the potential of our mRNA platform technology and develop novel cancer and infectious disease vaccines and therapeutics for patients,” said Brad Sorenson, MBA, Founder & Chief Executive Officer of Providence Therapeutics. “We are proud to have support from UHN as our partner and draw upon their renowned clinical research and discovery expertise and resources. We look forward to bringing safe and effective treatment options to Canadians.”
About Providence Therapeutics
Providence is a clinical-stage biotechnology company pioneering mRNA therapeutics and vaccines with a focus on infectious diseases and oncology. Initially founded as a cancer vaccines company in 2015, in response to a worldwide need for a COVID-19 vaccine, Providence expanded its focus beyond oncology therapies to develop an mRNA vaccine for COVID-19. Providence works with multiple industry collaborators, universities, nongovernmental agencies and multiple arms of the Government of Canada to discover and develop vaccines and treatments for infectious diseases and cancer. This has resulted in the development of an mRNA vaccine platform that includes a proprietary design algorithm and proprietary, scalable manufacturing processes. For more information, please visit providencetherapeutics.com.
A team led by Dr. Courtney Jones at the Princess Margaret Cancer Centre (PM) discovered that a protein involved in cellular metabolism called SIRT3 could serve as a therapeutic target for acute myeloid leukemia (AML).
AML is the most common type of blood cancer in adults and it arises from leukemia stem cells. These cells can divide and multiply to give rise to all types of cancer cells present in an individual patient.
"New AML treatments are needed that can target and kill leukemia stem cells to prevent relapse,” says Dr. Jones, a PM Scientist and an Assistant Professor at the University of Toronto’s Department of Medical Biophysics.
“In this study, we focused on a protein called SIRT3. Previous findings suggested that this protein is involved in how cancer cells produce energy and has been linked to AML survival. This led us to explore the idea of targeting it in leukemia stem cells—to see if we could essentially starve these treatment-resistant cells.”
As a first step, the researchers explored whether SIRT3 is important for the survival of leukemia stem cells. To test this, they shut down the expression of SIRT3 in experimental models of leukemia.
Image of study’s first author, Cristiana O’Brien, viewing cancer cells under a microscope.
“We could not have been happier with what we found. We discovered that SIRT3 was essential for the survival of human leukemia stem cells, and, importantly, we determined that it was not needed by normal blood stem cells,” says Cristiana O’Brien, a master’s student in Dr. Jones’ lab. “This finding has significant clinical implications, because it means that we can potentially target the cancer stem cells without harming healthy blood cells.”
Next, they delved deeper into the molecular mechanisms underlying SIRT3's role in leukemia stem cells. They discovered that SIRT3 supports energy production in these cells by regulating fatty acid oxidation.
The researchers also identified two ways to better target SIRT3 and kill leukemia stem cells. First, they found that disrupting the production and use of cholesterol in these cells made them more vulnerable to SIRT3 inhibition. Second, the researchers found that combining SIRT3 inhibition with a drug commonly used to treat AML called venetoclax led to an improved response.
"Our findings establish SIRT3 as a key regulator of fat metabolism and a potential therapeutic target in primitive AML cells,” says Dr. Jones. “This discovery opens up new avenues for developing targeted treatments—including combination therapies—that could improve the outcomes for patients with this deadly form of leukemia."
This work was supported by the University of Toronto, the National Institutes of Health, the Government of Ontario, the Ontario Institute of Cancer Research, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Terry Fox Research Institute, the University of Colorado, the Leukemia & Lymphoma Society, the American Society of Hematology and The Princess Margaret Cancer Foundation. Dr. John Dick holds a Tier 1 Canada Research Chair in Stem Cell Biology. Dr. Anastasia Tikhonova holds a Tier 2 Canada Research Chair in Stem Cell Niche Biology. Dr. Courtney Jones is an Assistant Professor of Medical Biophysics at the University of Toronto and holds a Tier 2 Canada Research Chair in Leukemia Stem Cell Metabolism.
Drs. Lin and Melnick received funding from the Falk Medical Research Foundation during the conduct of the study. Dr. Lin received other support from Sedec Therapeutics outside the submitted work. Dr. Melnick received funding from Janssen, Epizyme, Sanofi and Daiichi Sankyo, and personal fees from Janssen, Epizyme, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo and Exo Therapeutics outside of the submitted work; and a patent for 8635-01-US issued. Dr. Dick receives royalties from Trillium Therapeutics Inc, has a commercial research grant from Celgene/BMS and receives institutional licensing fees for AML models.
O'Brien C, Ling T, Berman JM, Culp-Hill R, Reisz JA, Rondeau V, Jahangiri S, St-Germain J, Macwan V, Astori A, Zeng A, Hong JY, Li M, Yang M, Jana S, Gamboni F, Tsao E, Liu W, Dick JE, Lin H, Melnick A, Tikhonova A, Arruda A, Minden MD, Raught B, D'Alessandro A, Jones CL. Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity. Haematologica. 2023 Apr 6. doi: 10.3324/haematol.2022.281894.
Five UHN researchers have been named winners of the inaugural Di Poce Research Scholar Awards, which support women-led transplantation research.
The awards represent a unique $2 million investment that will be split among recipients to cover research costs, enabling them to devote more time to their research programs.
“These awards are meant to promote the highest quality research and innovation from some of our talented and internationally recognized women faculty at the Ajmera Transplant Centre,” says Dr. Atul Humar, Director of UHN's Ajmera Transplant Centre. “The Ajmera Transplant Centre prides itself on efforts to promote equity, diversity and inclusion in all of our endeavors.”
UHN’s five award recipients are listed below:
● Dr. Ana Konvalinka, Senior Scientist at the Toronto General Hospital Research Institute (TGHRI), transplant nephrologist, and Director of the Ajmera Transplant Centre biobank for kidney, pancreas and liver transplant programs
● Dr. Tereza Martinu, Scientist at TGHRI, lung transplant respirologist and Clinician-Scientist with the Toronto Lung Transplant Program
● Dr. Nazia Selzner-Malekkiani, Clinician-Scientist and Medical Director of the Living Donor Liver Transplant Program at Ajmera Transplant Center
● Dr. Deepali Kumar, Clinician Investigator at TGHRI and Director of Transplant Infectious Diseases at UHN
● Dr. Golnaz Karoubi, Assistant Scientist at TGHRI
“Receiving this award means that I'll be able to devote more time to advancing transplant research and importantly, training the next generation of women researchers in transplant science,” says Di Poce recipient, Dr. Kumar whose research focuses on the prevention and treatment of viral infections post-transplant.
Dr. Golnaz Karoubi, whose work combines tissue engineering and stem cells to advance the development of bioartificial lungs and tracheas for transplantation, says, “I hope to be able to pay this forward by providing young women from under-represented groups with an opportunity to learn and apply exciting tissue engineering approaches to transplantation research.”
Fellow recipient Dr. Nazia Selzner says, “This award will allow me to have more protected time dedicated to my research, which is focused on developing methods to improve human livers that are currently rejected, so that we can expand the pool of donor organs available to patients.”
Dr. Ana Konvalinka says the Di Poce Award will help sustain and ignite her research in kidney transplants. Dr. Konvalinka is developing treatments to counteract antibody-mediated rejection in the kidney. She is also working to reduce kidney fibrosis, using cells and preclinical models of kidney scarring. Another aim of Dr. Konvalinka’s research program is to enhance the understanding of molecular mechanisms of kidney rejection and fibrosis.
Commenting on the funding, Dr. Tereza Martinu says, “One of my main goals with this award will be the mentorship of future investigators through the support of salaries and stipends of excellent research staff and trainees. This award will enable our team to advance our research focused on developing better biomarkers and therapies for lung graft scarring. We hope to move this research closer to clinical application, so that we can improve overall transplant outcomes.”
The awards were made possible thanks to the John Di Poce Family Fund, a generous philanthropic gift from Mr. John Di Poce and his family, who are longstanding supporters of the Ajmera Transplant Centre through their donations to the UHN Foundation.
Congratulations to all awardees!
Welcome to the latest issue of The Krembil.
The Krembil is the official newsletter of the Krembil Research Institute (formerly the Toronto Western Research Institute). Research at Krembil is focused on finding innovative treatments and cures for chronic debilitating disorders, including arthritis and diseases of the brain and eyes.
Stories in this month’s issue include:
● The Don Weaver Symposium: Krembil highlights the research, impact and legacy of its former Director, Dr. Donald Weaver.
● Excellence in Health Research: Neurosurgeon and Senior Scientist Dr. Gelareh Zadeh wins the Canada Gairdner Momentum Award.
● Interrupting Interactions: Researchers identify a protein interaction involved in Parkinson’s and a way to disrupt it.
● Promising New Therapy: New treatment for glioblastoma prolongs patient survival in an early-phase clinical trial.
● Why Immune Cells Attack: New research reveals how the body generates damaging autoantibodies in lupus.
● An Unexplored Mechanism: Study identifies a key cause of abnormal neuron development in 15q13.3 microdeletion syndrome.
Read these stories here. To read previous issues, see the newsletter archive.
Welcome to the latest issue of Research Spotlight.
As Canada’s largest research hospital, UHN is a national and international source for discovery, education and patient care. This newsletter highlights top research advancements from over 5000 members of TeamUHN—a diverse group of trainees, staff, and principal investigators that conduct research at UHN.
Stories in this month’s issue:
● Improving Radiation Therapy: Made-in-Toronto tool ensures the precise delivery of radiation and is now used world-wide.
● Interrupting Interactions: Researchers identify a protein interaction involved in Parkinson’s and a way to disrupt it.
● Kidney as Key to Fighting Obesity: Study implicates the kidney as a new target for developing weight loss and obesity therapies.
● Learning Through Practice: Medical residents feel that interacting with patients is the best way to hone their communication skills.
Read these stories and more online here. To read previous issues, see the newsletter archive.
Researchers led by Dr. Karun Singh at UHN’s Donald K. Johnson Eye Institute (DKJEI) have identified a molecular mechanism underlying brain dysfunction in 15q13.3 microdeletion syndrome.
15q13.3 microdeletion syndrome is a genetic disorder in which an individual is missing a group of genes located on chromosome 15. The syndrome is linked to multiple conditions, including autism spectrum disorder, intellectual disability, epilepsy and schizophrenia.
“Previous studies have identified DNA changes that contribute to 15q13.3 microdeletion syndrome, but we do not know how these changes result in abnormal brain function,” explains Dr. Singh, a Senior Scientist at DKJEI and the senior author of the study. “Because of this gap in our knowledge, there are no targeted treatments for 15q13.3 microdeletion syndrome, or related disorders.”
One gene that has been implicated in the microdeletion syndrome—called OTUD7A—stands out due to its role in neuronal maturation and connectivity and its link to brain disorders such as epilepsy. Although researchers know that OTUD7A is important for brain development, its exact functions are largely unknown.
“We wanted to determine the role of OTUD7A in 15q13.3 microdeletion syndrome at the cellular level—how it influences proteins within neurons to cause brain abnormalities,” says Dr. Brianna Unda, a former postdoctoral researcher in Dr. Singh’s lab and the lead author of the study.
Using experimental models and patient samples, the team compared neurons with and without functional OTUD7A genes. They discovered that neurons defective for OTUD7A did not grow, mature or connect with other neurons as well as those that had an intact gene.
“This finding implicates OTUD7A in neuronal development and suggests that changes in this gene underlie the symptoms of 15q13.3 microdeletion,” says Dr. Unda.
To determine how OTUD7A contributes to neuronal development and function, the researchers developed a technique to map protein interactions within neurons. They found that OTUD7A—the protein encoded by the OTUD7A gene—interacts with Ankyrin-G—a protein that is involved in neuron function and has been linked to autism spectrum disorder and epilepsy.
Based on these results, the team took a deeper look at Ankyrin-G and discovered that neurons with 15q13.3 microdeletion had lower levels of the protein. They also found that the Ankyrin-G that was present was less stable in these cells compared to those without the microdeletion. Importantly, they could reverse the neuronal abnormalities seen in 15q13.3 microdeletion syndrome by restoring normal levels of Ankyrin-G.
These findings suggest a sort of domino effect in which 15q13.3 microdeletion leads to loss of OTUD7A. Loss of OTUD7A then leads to reduced levels and stability of Ankyrin-G. And, finally, loss of Ankyrin-G disrupts neuronal development and connectivity.
This study provides important insights into the disease mechanisms of 15q13.3 microdeletion syndrome and the role of OTUD7A-Ankyrin-G interactions in neuronal development. “This is an exciting step forward for understanding neurodevelopmental disorders. By identifying key molecular pathways involved in microdeletion syndromes, our research is laying a strong foundation that could unlock future targeted therapeutics and preventative strategies,” says Dr. Singh.
This work was supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Ontario Brain Institute, the Network of European Funding for Neuroscience Research and the UHN Foundation. Dr. Karun Singh is an Associate Professor in the Department of Ophthalmology and Vision Sciences at the University of Toronto.
Unda BK, Chalil L, Yoon S, Kilpatrick S, Irwin C, Xing S, Murtaza N, Cheng A, Brown C, Afonso A, McCready E, Ronen GM, Howe J, Caye-Eude A, Verloes A, Doble BW, Faivre L, Vitobello A, Scherer SW, Lu Y, Penzes P, Singh KK. Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome. Mol Psychiatry. 2023 Jan 6. doi: 10.1038/s41380-022-01937-5.
A study published in JAMA and led by researchers at the Toronto General Hospital Research Institute (TGHRI) has provided a new way to conduct clinical trials that enable treatments to be better tailored to individual patients.
“By rethinking how we analyzed clinical trial data, we found a new strategy that could unlock personalized treatments,” says Dr. Ewan Goligher, TGHRI Scientist and the lead author of the study.
The study that was conducted helped to unravel the differing effects of the anticoagulant heparin in individuals hospitalized for COVID-19. Heparin is widely used to prevent and treat blood clots in patients with COVID-19.
“We observed conflicting results between moderate and severely ill patients from previous randomized clinical trials and knew that there was a need to delve deeper into why treatment responses varied,” explains Dr. Goligher.
To address this knowledge gap, the researchers carried out an international randomized clinical study to assess the effectiveness of heparin to prevent blood clots compared to standard treatments. The study included 3320 patients from around the world that were hospitalized for COVID-19 between April 2020 and January 2021.
"An innovative aspect of this study is that we meticulously analysed the data through three different approaches, each of which provided us with a unique perspective on the effects of the treatment," explains Dr. Patrick R. Lawler, TGHRI Scientist and second author of the study.
Typically, medical trials compare the overall effect between treatment and control groups, known as the 'average treatment effect'. However, individual responses can vary greatly. The challenge is to identify which patients benefit without resorting to guesswork. This study is the first to employ and compare two new cutting-edge methods for analyzing trials: one based on modeling the risk of complications and the other on using machine learning to identify patients that can benefit from the treatment.
The findings consistently revealed specific patterns across the different data analyses that were carried out. Dr. Goligher elaborates, “Patients who did not require organ support demonstrated potential benefits, as did women and those with lower body weight. Conversely, patients with higher body weight and those requiring organ support were more likely to experience negative effects.”
“The success of this trial reveals a path towards optimizing treatment decisions in individual patients and suggests that our approach could be applied to clinical trials for other treatments and diseases. This new approach could have wide-reaching impacts by improving treatments and the health of patients worldwide,” adds Dr. Goligher.
This work was supported by the Platform foR European Preparedness Against (Re-)emerging Epidemics (PREPARE) Consortium, the Rapid European Covid-19 Emergency Response research (RECOVER) Consortium, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, the Canadian Institutes of Health Research, the National Institute for Health and Care Research, the NIHR Imperial Biomedical Research Centre (BRC), the Health Research Board of Ireland, the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health, the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, the Wellcome Trust Innovations Project and the UHN Foundation. Dr. Goligher is an Assistant Professor at the Interdepartmental Division of Critical Care Medicine at the University of Toronto.
Dr. Goligher, Dr. Lawler, Mr. Jensen, Dr. L.R. Berry, Dr. Lorenzi, Dr. S. Berry, Dr. McVerry, Dr. Bradbury, Dr. Berger, Dr. Castellucci, Dr. Kornblith, Dr. Gordon, Dr. McArthur, Dr. Hochman, Dr. Neal, and Dr. Zarychanski have reported financial support from a variety of organizations and companies. For full details, please see the ‘Conflict of Interest Disclosures’ section in the research article.
Goligher, E. C., Lawler, P. R., Jensen, T. P., Talisa, V., Berry, L. R., Lorenzi, E., McVerry, B. J., Chang, C. H., Leifer, E., Bradbury, C., Berger, J., Hunt, B. J., Castellucci, L. A., Kornblith, L. Z., Gordon, A. C., McArthur, C., Webb, S., Hochman, J., Neal, M. D., Zarychanski, R., … REMAP-CAP, ATTACC, and ACTIV-4a Investigators (2023). Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19. JAMA, 329(13), 1066–1077. DOI: 10.1001/jama.2023.3651
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