Krembil Brain Institute researchers have developed an experimental model for early-stage Parkinson disease using Caenorhabditis elegans, a small transparent worm. They also incorporated the model into a drug-screening pipeline to rapidly identify potential therapies for Parkinson disease.
Currently, experimental models of early-stage Parkinson disease are limited. Such models are needed for the discovery of new therapies. A research team led by Drs. Lorraine Kalia and Suneil Kalia explored whether the roundworm C. elegans could be used to address this issue. C. elegans is particularly well-suited for studying neurons because scientists have mapped this animal’s nervous system in exquisite detail.
Parkinson disease is associated with the accumulation of the protein alpha-synuclein in neurons. The protein can kill the neurons that control movement. Because these cells do not regenerate, researchers are looking for ways to detect and treat the disease in its early stages.
“Our C. elegans model has an alpha-synuclein defect that causes motor dysfunction—worms with this defect coil up much more frequently than worms without it. At the molecular level, the neuronal processes that occur in these worms are similar to those that occur in humans with early-stage Parkinson disease,” says Dr. Lorraine Kalia, Senior Scientist at the Krembil Brain Institute.
Coiling behaviour of a C. elegans roundworm with the alpha-synuclein defect. Video taken by Kevin Chen, the lead author of the study.
The team used artificial intelligence to rank a library of drugs approved for human use based on their potential to reduce alpha-synuclein accumulation. They next tested the six most promising drugs using the C. elegans model. The team found that five of the drugs reduced the frequency of the worms’ coiling behaviour. The team then tested these drugs in mammalian models in the lab to determine which could prevent alpha-synuclein from killing brain cells. Using this approach, the researchers identified the antibiotic rifabutin as a potential treatment option.
“Most experimental models of Parkinson disease that are used for drug discovery do not have measurable markers of neuron degeneration caused by alpha-synuclein in the early stages of the disease, before the neurons are lost,” says Dr. Suneil Kalia, Senior Scientist at the Krembil Brain Institute. “Coupled with artificial intelligence technologies, our C. elegans model has the potential to be scaled up and help identify drugs that might treat the disease in humans.”
“It is important to note that Parkinson disease is very complex, and a single experimental model cannot capture all of its features,” adds Dr. Lorraine Kalia. “Our multi-step drug screening strategy combines complementary experimental models so that we can rapidly translate potential drugs to human clinical trials.”
This work was supported by the Natural Sciences and Engineering Research Council of Canada, Ontario Brain Institute, Parkinson's UK and UHN Foundation. Dr. Lorraine Kalia is an Associate Professor of Medicine at the University of Toronto. Dr. Suneil Kalia is an Associate Professor of Surgery at the University of Toronto.
Chen KS, Menezes K, Rodgers JB, O'Hara DM, Tran N, Fujisawa K, Ishikura S, Khodaei S, Chau H, Cranston A, Kapadia M, Pawar G, Ping S, Krizus A, Lacoste A, Spangler S, Visanji NP, Marras C, Majbour NK, El-Agnaf OMA, Lozano AM, Culotti J, Suo S, Ryu WS, Kalia SK, Kalia LV. Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans. Mol Neurodegener. 2021 Nov 12. doi: 10.1186/s13024-021-00497-6.
Researchers at UHN’s Ajmera Transplant Centre and Toronto General Hospital Research Institute have been awarded a transformative grant of $24 million to advance ex vivo technology to repair and rebuild organs for all patients in need.
The project, led by the Director of the Toronto Lung Transplant Program, Dr. Shaf Keshavjee, is one of only seven across Canada selected to receive the prestigious New Frontiers in Research Fund (NFRF) – Transformation funding, following a comprehensive international consultation.
“The Ex Vivo Lung Perfusion (EVLP) system we developed here in Toronto has revolutionized lung transplantation in the past decade. Now, it’s been translated around the world to increase lung transplant access and it’s being extended to other organs,” explains Dr. Keshavjee, Principal Investigator of the project, who is also UHN’s Surgeon-in-Chief and Vice Chair for Innovation, in the Department of Surgery at the University of Toronto (UofT).
Over the course of this project, the team of over 20 researchers at UHN, national and international partner sites will develop sophisticated ex vivo platforms to:
● Increase organ preservation from hours to days;
● Improve the immune response and organ tolerance for transplant recipients;
● Advance precision medicine to customize organs to each individual patient’s needs;
Specific research activities include the development of gene therapy to make an organ more compatible with a recipient to prevent organ rejection by the immune system. Another example is the use of light therapies to eliminate viral or bacterial infections in donated organs so that they can be considered for transplant. The funding will also enable the team to refine and improve equitable organ allocation guidelines for all patients.
“Not only will it enable longer preservation, this research will let us treat and improve organs. It has the potential to change the paradigm in the field of transplantation,” says Dr. Marcelo Cypel, Surgical Director of the Ajmera Transplant Centre, and a co-Principal Investigator of the project.
Dr. Brad Wouters, UHN’s Executive Vice President, Science and Research, adds, "The advancements that this team has made and their continued success made possible by support from provincial and federal governments, industry partners, external charitable agencies, generous philanthropy from the UHN Foundation and our incredible patient partners. This award recognizes the tireless efforts of the team, and this support, which have been key to achieving global impact."
Dr. Keshavjee is a founder, shareholder, and Chief Medical Officer of Traferox Technologies Inc. and a consultant for Lung Bioengineering. Dr. Cypel is a founder and shareholder of Traferox Technologies and a consultant for Lung Bioengineering.
NFRF was designed to support large-scale, Canadian-led interdisciplinary research projects with the potential to realize real and lasting change. It is under the strategic direction of the Canada Research Coordinating Committee and administered by the Tri-agency Institutional Programs Secretariat on behalf of Canada’s three research granting agencies: the Social Sciences and Humanities Research Council, the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council.
The Government of Canada has announced the latest round of Canada Research Chair funding. Congratulations to the following three UHN scientists, who received new or renewed funding from the Canada Research Chairs (CRC) program:
Dr. Daniel De Carvalho, Tier 2 Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy (renewal). Dr. De Carvalho is a Senior Scientist at the Princess Margaret Cancer Centre whose research is focused on new therapies for colorectal cancer. This Chair will help advance his research on a new strategy to stimulate the immune system to target cancer called ‘viral mimicry’. The process involves activating the production of molecules that trick the immune system into seeing cancer as an infection that needs to be destroyed. Dr. Carvalho will also advance the development of blood tests to monitor and diagnose colorectal cancer using epigenetics combined with machine learning.
Dr. Thomas Kislinger, Tier 1 Canada Research Chair in Cancer Precision Medicine (advancement). Dr. Kislinger is a Senior Scientist at the Princess Margaret Cancer Centre and a world leader in the application of proteomics and biomarkers for cancer treatment. Funding from this Chair will enable his team to advance anticancer therapies that can be tailored to individual patients. His program will achieve this by developing advanced mass spectrometry-based approaches to rapidly identify the proteins present in blood, combined with ‘cell surface capturing’ technologies to take snapshots of the surface of cells. He will explore these approaches to identify aggressive prostate, head and neck, and ovarian cancers.
Dr. Sonya MacParland, Tier 2 Canada Research Chair in Liver Immunobiology (new). Dr. MacParland is a Scientist at the Toronto General Hospital Research Institute and an emerging world leader in liver biology. Funding from this Chair will enable her team to study the cellular basis of liver disease and to harness populations of cells identified within the liver to promote liver health. This work will build on Dr. MacParland’s role in leading the first international effort to create a publicly available single-cell and molecular-level map of the human liver, which is providing unprecedented insight into how the liver functions. Her team will build on these discoveries to develop nanoparticle-based therapies as well as strategies to modulate immune cells to treat viral-related liver disease.
The results were announced by the Honourable François-Philippe Champagne, Minister of Innovation, Science and Industry, during a virtual event (January 12, 2022). The funding results were for the CRC 2020-2 cycle and represented a total of approximately $151 million to support 188 new and renewed Chairs at 43 research institutions across Canada.
Congratulations to Drs. De Carvalho, Kislinger and MacParland!
For more info, see the official press release.
Researchers at the Donald K. Johnson Eye Institute have revealed that an eye-preserving surgical procedure is a safe and effective approach to treating retinoblastoma.
Retinoblastoma is a rare and aggressive cancer that forms in the retina—the light-sensitive tissue at the back of the eye. Standard treatments include chemotherapy, laser therapy and radiation. If these treatments fail, the eye is often removed to prevent the cancer from spreading.
Organ-preserving surgery, in which the tumor and a small portion of surrounding tissue are removed, is not used to treat retinoblastoma for fear that portions of the cancer will remain and spread.
“Recent technical advances have greatly improved the safety of eye surgery for retinoblastoma,” explains Dr. Brenda Gallie, the senior author of the study and an Affiliate Scientist at the Donald K. Johnson Eye Institute. “Given these advances, our research team performed eye-preserving surgery, called tylectomy, as a secondary treatment to save vision in children for whom standard chemotherapy was not effective.”
To determine the safety and effectiveness of the surgery, Dr. Gallie’s team examined data from 919 children (1171 eyes) who received standard treatments alone, standard treatments plus tylectomy or eye removal. All children were treated by a single team in China, which included retinoblastoma specialist, Dr. Junyang Zhao, and vitreoretinal surgeon, Dr. Qiyan Li, co-first authors of the study.
The researchers found that the percentage of children who eventually needed eye-removal surgery was reduced from 47% with standard treatments alone to 20% with standard treatments plus tylectomy.
Furthermore, the five-year overall survival rate for children who underwent tylectomy was nearly 94%. This survival rate is significantly higher than that of children who received standard treatments alone (89%) and similar to that of children who had immediate eye removal (95%).
Children who received tylectomy were no more likely to experience lethal cancer spread than those who had immediate eye removal, and they were nearly three times less likely to die of cancer spread than those who received standard treatments alone.
These findings suggest that tylectomy is a safe and effective treatment for retinoblastoma, and that it should be made available to more patients in combination with standard therapies.
“The children that we treat are unbelievably resilient and they motivate us to keep working to improve therapies,” says Dr. Gallie. “Our findings reveal that we can safely remove tumours surgically without sacrificing the entire eye—an insight that has the potential to help children with retinoblastoma around the world.”
This work was supported by the UHN Foundation.
Zhao J, Li Q, Feng ZX, Zhang J, Wu S, Jin L, Gallie BL. Tylectomy Safety in Salvage of Eyes with Retinoblastoma. Cancers (Basel). 2021 Nov 22. doi: 10.3390/cancers13225862.
Congratulations to Dr. Eleanor Fish for being named a Member of the Order of Canada. This prestigious distinction—one of the country’s highest civilian honours—recognizes her groundbreaking immunology research and efforts to advance the development of broad-spectrum antiviral therapeutics.
Dr. Fish is Emerita Scientist at UHN’s Toronto General Hospital Research Institute. She is a Professor in the Department of Immunology, and the Associate Chair of International Initiatives & Collaborations at the University of Toronto.
A world-renowned immunologist, Dr. Fish is an expert in several infectious diseases including SARS, H1N1 and Ebola. Her research has shed light on how cytokines, including interferons and other naturally occurring proteins, function as part of the immune system and their therapeutic potential.
She has conducted various studies exploring the therapeutic potential of interferon treatment for SARS, avian H5N1, pandemic H1N1 influenza and ebola—many of which have shown positive outcomes for patients. Most recently, in an exploratory clinical study in Wuhan, China at the start of the pandemic, she evaluated the therapeutic effectiveness of inhaled interferon treatment for COVID-19. Promising findings showed accelerated viral clearance and reduced lung abnormalities, leading to a number of subsequent and ongoing international clinical trials.
In addition to her academic achievements, Dr. Fish founded the international not-for-profit Beyond Sciences Initiative. The program is helping to build capacity in science and technology among young scholars by promoting access to academic knowledge, cultural understanding and collaboration.
The Order of Canada was created in 1967 to recognize people whose service, innovations and compassion shape Canadian society, foster imagination and unite people and communities.
Nationally, a total of 135 appointments and promotions were announced on December 29, 2021 by the Governor General of Canada, Her Excellency the Right Honourable Mary Simon.
To see the full list of appointees, read Governor General’s press release.
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 across UHN and from over 1000 researchers appointed at our institutes.
Stories in this month’s issue:
● Light at the End of the Tunnel: Cells transplanted into the retina transfer materials to recipient cells through nanotubes.
● Pancreatic Cancer Complexity: Study reveals how the distinct microstructure within a tumour affects cancer cell behaviour.
● Not Made for Winter: Mobility scooters are not up to the challenges of Canadian winters.
● Breaking Down Barriers: UHN study reveals how systemic racism impacts careers of foreign trained health professionals.
Researchers at the University Health Network have identified a new target that may increase the effectiveness of cancer immunotherapy by focusing on the metabolism of T cells.
Immunotherapy has been a major game changer in the treatment of cancer. Nonetheless, some tumors fail to respond to the treatment, which has prompted researchers to search for new ways to improve its effectiveness.
Studies have shown that metabolic and energetic processes within T cells are linked to their ability to kill cancer and inhibit tumor growth. Therefore, leveraging these processes may be a promising approach to enhance the efficacy of immunotherapy.
To understand this further, a team led by Dr. Pamela Ohashi, Senior Scientist and Director of the Tumor Immunotherapy Program at the Princess Margaret Cancer Centre, performed an in depth analysis of the metabolic pathways in three different subsets of T cells with varying anti-tumor properties.
They discovered that T cells with the strongest anti-tumor activity had an increased expression of a metabolic pathway known as the pantothenate/coenzyme A (CoA) pathway.
Treating T cells with CoA led to an increase in their energy-production and enhanced their anti-tumor function.
“The discovery that a single molecule involved in metabolism can have a profound impact on the function and anti-tumor activity of a T cell was an exciting finding,” explains Dr. Michael St Paul, postdoctoral fellow and co-first author of the study.
Further, in preclinical experimental models, treatment with the pantothenate, a precursor to CoA, was able to improve the effectiveness of immunotherapy and increase overall survival.
“To determine if these findings were applicable in the clinical setting, we looked at these pathways in advanced melanoma patients,” says Dr. Sam Saibil, Medical Oncologist and co-first author of the study. “What we found was that those patients with higher blood levels of pantothenate prior to undergoing treatment, had a better response to immunotherapy.”
“This work revealed a new role for the pantothenate/coenzyme A (CoA) pathway in promoting anti-tumor immunity and lays the foundation for future studies that explores whether manipulating this metabolic pathway in T cells can improve the efficacy of immunotherapies,” says Dr. Ohashi.
This work was supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and The Princess Margaret Cancer Foundation. Dr. Trevor Pugh holds a Tier 2 Canada Research Chair in Translational Genomics. Dr. Pamela Ohashi is a Professor of Immunology at the University of Toronto and holds a Tier 1 Canada Research Chair in Autoimmunity and Tumour Immunity.
St. Paul M, Saibil SD, Han SJ, Israni-Winger K, Lien SC, Laister RC, Sayad A, Penny S, Amaria RN, Haydu LE, Garcia-Batres C, Kates M, Mulder DT, Robert-Tissot C, Gold MJ, Tran CW, Elford AR, Nguyen L, Pugh TJ, Pinto DM, Wargo J, Ohashi P. Coenzyme A fuels T cell antitumor immunity. Cell Metab. 2021 Dec 7. DOI: 10.1016/j.cmet.2021.11.010.
Research conducted at UHN's research institutes spans the full spectrum of diseases and disciplines, including cancer, cardiovascular sciences, transplantation, neural and sensory sciences, musculoskeletal health, rehabilitation sciences, and community and population health.
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