Pharmacology

Two teams of researchers at the University of Toronto have partnered with Moderna Canada to advance new mRNA-based therapies for HIV and other diseases.

The projects – one led by Mario Ostrowski, an infectious disease physician at Unity Health Toronto and a professor of medicine, immunology and pathobiology and lab medicine at the Temerty Faculty of Medicine; and the other by Haissi Cui, assistant professor in the department of chemistry in the Faculty of Arts & Science, and Landon Edgar, assistant professor in the department of pharmacology and toxicology in the Temerty Faculty of Medicine and an investigator in the PRiME research group – are supported through the partnership framework agreement between �鶹ֱ��app and Moderna.

Launched in April 2022, this partnership was the first between Moderna and a Canadian university and provides opportunities for �鶹ֱ��app researchers to collaborate with a leading biotechnology firm to create new tools to prevent and treat diseases.

“The partnership between the University of Toronto and Moderna Canada is a testament to the power of industry and academic collaborations, and one that will advance the frontier of mRNA-based vaccines and therapies,” said Derek Newton, assistant vice-president, innovation, partnerships and entrepreneurship at �鶹ֱ��app.

“Researchers from both organizations have a shared vision to create new health-care innovations to prevent and treat infectious diseases that will impact patients across Canada and globally.”

From left: Researchers Mario Ostrowski, Haissi Cui and Landon Edgar will be working on projects supported through the partnership framework agreement between �鶹ֱ��app and Moderna (supplied photos)

Ostrowski’s project brings together his decades of research on the immune response to HIV with Moderna’s expertise in mRNA vaccines to develop personalized mRNA vaccines to treat HIV infection.

This strategy could address one of the biggest challenges in HIV management: the long-term persistence of viral reservoirs within immune cells in the body, which necessitates life-long antiretroviral therapy treatments for people with HIV. While these therapies help people with HIV live longer, they can also lead to side effects that negatively impact a person’s overall physical and mental health.

To tackle this challenge, the researchers will design mRNA vaccines that are tailored to the unique strain of HIV found in each person. Ostrowski believes that these highly targeted vaccines can activate powerful immune cells to seek out and eliminate hidden viral reservoirs. Similar approaches have been used successfully to create personalized therapeutic vaccines for people with cancer.

This work will also leverage the capabilities of the Toronto High Containment Facility (THCF), which is equipped to allow researchers to study high-risk pathogens, such as HIV and SARS-CoV-2, in a safe and secure way. The facility is a cornerstone of the Emerging and Pandemic Infections Consortium (EPIC) institutional strategic initiative, a partnership between �鶹ֱ��app and five major Toronto hospitals to advance innovative infectious disease research and strengthen preparedness for future pandemics.

Containing the only containment level 3 (CL3) research lab in the Greater Toronto Area and the largest in the province, the THCF plays a critical role in supporting Ontario’s life sciences research ecosystem. Its unique infrastructure and capabilities enable cutting-edge research on vaccines and therapeutics and provide training opportunities needed to drive innovation and biomanufacturing in Ontario.

Modulating the body’s immune response is also at the core of the project led by Cui and Edgar.

Their work focuses on the sugars that coat the outside of all immune cells. These sugars, called glycans, have recently been shown to play an important role in fine-tuning the function of some immune system components. However, designing targeted and effective therapies to modulate the glycans themselves has remained elusive.

In collaboration with Moderna, Cui and Edgar will develop mRNA technologies that can be used to adjust glycan levels within specific tissues – or even on specific cell types. If successful, this approach could be used to alter how immune cells function in a myriad of diseases.

Through this cross-faculty and cross-sector collaboration, Cui and Edgar’s work would demonstrate the feasibility of using these cutting-edge technologies to manipulate the architecture of a cell’s surface and to improve immune responses through cell-surface engineering.

“At Moderna, we are focused on the creation of transformative mRNA medicines. For the past 13 years, we have been investing in research and innovation into different facets of mRNA science,” says Patricia Gauthier, Moderna Canada president and general manager.

“Our collaboration with the University of Toronto and its exceptional scientists further strengthens our resolve to push the boundaries of what can be achieved in this rapidly evolving field to improve the lives of patients through mRNA science.”

As part of the partnership, each team will be paired with a scientific expert at Moderna who can champion their research and provide support and feedback.

The selection of these two projects follows the announcement in October 2022 of a partnership between Moderna and a team of �鶹ֱ��app researchers led by Omar F. Khan, an assistant professor in the Institute of Biomedical Engineering, to develop next-generation RNA platform technologies. The project recently received support from the Natural Sciences and Engineering Research Council of Canada Alliance Grant program, which aims to foster collaborations between university researchers and partner organizations in the private, public and not-for-profit sectors.

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Leukemia drugs may help patients with treatment-resistant lung cancer: �鶹ֱ��app researchers

Christopher.Sorensen — Mon, 24 Feb 2020 16:42:25 +0000

Leukemia drugs may help patients with treatment-resistant lung cancer: �鶹ֱ��app researchers

Christopher.Sorensen Mon, 02/24/2020 - 11:42

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Lung cancer poses a major challenge for new targeted therapies because of drug resistance, but a new study involving �鶹ֱ��app researchers suggests leukemia drugs could offer new treatment options (photo via Wikimedia Commons)

Jovana Drinjakovic

Topic

Breaking Research

Donnelly Centre for Cellular & Biomolecular Research

Hospital for Sick Children

Molecular Genetics

Mount Sinai Hospital

Pharmacology

Princess Margaret Hospital

Research & Innovation

University Health Network

Two recently approved leukemia drugs could be enlisted against treatment-resistant lung cancer, with a clinical trial for one of them expected to launch later this year in Toronto and Zagreb, Croatia.

Researchers at the University of Toronto, led by Igor Stagljar, a professor of molecular genetics and biochemistry at the Donnelly Centre for Cellular and Biomolecular Research, made the findings using a new live cell-based method developed by his team for identifying small molecules that target specific mutations in cancer cells.

The findings were published in the journal Nature Chemical Biology.

“Drug resistance is a big problem for lung cancer patients,” says Stagljar. “Our new technology allows us to find molecules that could be used against cancers for which no other treatment options are available.”

The researchers identified gilteritinib and midostaurin – two drugs already approved for patients with a particular form of leukemia – as potential treatments for lung cancer patients with triple mutant epidermal growth factor receptor (EGFR). The tumours in these patients are highly resistant to available therapy.

The Toronto team hopes to demonstrate the efficacy of these drugs in patient trials, with the gilteritinib trial to launch first. If it proves successful, gilteritinib could in a few years become a new standard-of-care treatment for an estimated 60,000 lung cancer patients worldwide who have triple mutant EGFR.

“We already have a sense of gilteritinib doses that are safe to give to humans,” says Dr. Adrian Sacher, an oncologist at the Princess Margaret Cancer Centre, at University Health Network, and an assistant professor of immunology at �鶹ֱ��app who will lead the trial. “We only need to demonstrate efficacy and hopefully make them a novel treatment option for lung cancer patients that have developed resistance to current targeted therapies.”

Lung cancer remains a leading cause of death from cancer in Canada and the world. Non-small cell lung cancer is the most common type of the disease, with about one fifth of cases in North America caused by EGFR mutations.

EGFR is a cell surface receptor that regulates cell proliferation and belongs to a class of proteins known as receptor tyrosine kinases (RTKs). Oncogenic mutations make the receptor overactive, spurring on cell division.

There are dozens of approved kinase inhibitor drugs that target specific mutations in the receptor’s catalytic domain, but tumours quickly gain new mutations and become drug resistant. A third of lung cancer patients on osimertinib, a last resort drug approved in 2017 against the double mutant EGFR, will develop the treatment-resistant C797S mutation within six to nine months.

“Our new technology allows us to find molecules that could be used against cancers for which no other treatment options are available,” says Igor Stagljar, a professor of molecular genetics and biochemistry at the Donnelly Centre for Cellular and Biomolecular Research (photo by Sam Motala)

In a bid to stay one step ahead of the disease, scientists seek to identify drugs that can target the mutations which arise in response to treatment. However, most methods are test tube-based and focus on finding new kinase inhibitors. Consequently, promising drug candidates are often not suitable as therapeutics because they don’t penetrate the cells well or because their effects are altered by other cellular factors.

The tool developed by Stagljar’s team overcomes these hurdles by testing potential drug molecules directly in living cells. Named MaMTH-DS, for Mammalian Membrane Two-Hybrid Drug Screen, the all-in-one method allows identification of drug candidates that both enter the cells and target the receptors in their natural environment.

“The advantage of our method is that we are doing it in living cells, where we have all the other molecular machineries present that are important for signal transduction,” says Stagljar. “Also, the compounds are fished at very low dose, which allows us to test for both permeability and toxicity at the same time.”

MaMTH-DS allows identification of drug molecules that target not only the receptor’s kinase activity, but also its interactions with other cellular proteins.

In a proof of principle study, the team looked for small molecules that can target the resistance-conferring C797S mutation in the triple mutant EGFR. A screen of almost 3,000 molecules revealed four promising compounds that had no effect on the normal receptor, meaning the drugs would be less likely to harm healthy cells.

In addition to midostaurin and gilteritinib, the latter of which will be tested in a pilot trial of about 20 lung cancer patients whose tumours harbor the C797S mutation, the study also revealed two more promising molecules.

One of these molecules, known as EMI1, acts on the mutant EGFR in a completely new way – not by inhibiting its kinase activity, but by targeting the receptor for degradation with the help of other molecular machineries. The researchers think that EMI1’s more complex mechanism of action will make it more difficult for tumours to develop resistance to it.

Stagljar is working with Rima Al-awar, an associate professor in �鶹ֱ��app's department of pharmacology and toxicology, and the head of therapeutic innovation and drug discovery at the Ontario Institute for Cancer Research (OICR), and her medicinal chemistry team to create an improved version of the EMI1 molecule before its ability to shrink tumours can be evaluated in animal cancer models and eventually patients.

"The unbiased screening approach by the Stagljar's group has the merit of identifying small molecule inhibitors that could act via new mechanisms of action that would otherwise escape detection by conventional drug development strategies, as shown in this proof of principle study, " says Marino Zerial, the managing director of the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. Zerial is one of Stagljar’s collaborators.

The research also included collaborators from the Hospital for Sick Children and Sinai Health System’s Lunenfeld-Tanenbaum Research Institute, as well as Utrecht University in the Netherlands, the Department for Lung Diseases Jordanovac in Zagreb, Croatia, Mediterranean Institute for Life Sciences in Split, Croatia and Yale Cancer Center.

The research was supported by funding from the Canadian Institute of Health Research, Genome Canada and the Ontario Research Fund, among others

From healthy babies to green energy storage: �鶹ֱ��app researchers share $9 million in new funding

rahul.kalvapalle — Tue, 03 Sep 2019 19:12:30 +0000

From healthy babies to green energy storage: �鶹ֱ��app researchers share $9 million in new funding

rahul.kalvapalle Tue, 09/03/2019 - 15:12

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Deborah O’Connor (right) is one of 32 �鶹ֱ��app researchers to receive Canada Foundation for Innovation funding. She's working with Richard Bazinet (left) and others to develop new technologies to process donor milk for babies (photo by Geoffrey Vendeville)

Rahul Kalvapalle

Topic

Our Community

Pediatrics

Cell and Systems Biology

Munk School of Global Affairs & Public Policy

Biochemistry

Centre for Addiction and Mental Health

Chemical Engineering

Chemistry

Factor-Inwentash Faculty of Social Work

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Faculty of Dentistry

Faculty of Kinesiology & Physical Education

Faculty of Medicine

Hospital for Sick Children

Immunology

Institute of Biomaterials and Biomedical Engineering

Laboratory Medicine and Pathobiology

Leslie Dan Faculty of Pharmacy

Mechanical & Industrial Engineering

Molecular Genetics

Munk School of Global Affairs & Public Policy

Nutritional Sciences

Pharmacology

Physics

Princess Margaret Hospital

Psychiatry

Psychology

Research & Innovation

St. Michael's Hospital

Sunnybrook Hospital

�鶹ֱ��app Scarborough

University Health Network

Babies born very prematurely face a serious nutritional challenge since their mothers are often unable to produce sufficient breast milk, a problem the University of Toronto's Deborah O’Connor is looking to tackle by testing cutting-edge technologies for processing pasteurized donor milk.

O’Connor, a professor and interim chair of the department of nutritional sciences in the Faculty of Medicine, is one of 32 �鶹ֱ��app faculty members who are sharing $9.1 million in federal funding via the Canada Foundation for Innovation’s John R. Evans Leaders Fund.

The fund, named for �鶹ֱ��app President Emeritus John R. Evans, aims to support researchers' infrastructure and equipment needs.

“Donor milk really helps with babies’ early hospital course, but the technology used to process this milk is very old,” said O’Connor. “This award will help us replace that technology with new equipment so we can evaluate its impact on retaining important nutrients and bioactive components in human milk.”

O’Connor’s research, carried out in collaboration with Professor Harvey Anderson and Associate Professor Richard Bazinet, both from the department of nutritional sciences, also explores the impact of sugar-sweetened beverages, plant-based beverages and cow’s milk on children’s appetite regulation and body composition as part of a broader investigation into how milk can be leveraged to improve the health of Canadians.

Vivek Goel, vice-president, research and innovation, and strategic initiatives, emphasized the impact the funding could have on projects like O’Connor’s, and on the university as a whole.

“We are incredibly proud that �鶹ֱ��app had so many important research projects funded by the John R. Evans Leaders Fund,” Goel said. “The support from the federal government will ensure that our researchers have access to research facilities that enable them to continue tackling the most pressing challenges of the day, and support us to attract diverse scholars from around the world.”

“Researchers in Canada know that cutting-edge tools and labs are necessary to make discoveries and innovate,” said federal Minister of Science and Sport Kirsty Duncan. “That is why our government is announcing funding for the infrastructure needs of Canadian researchers.

“Their groundbreaking contributions to science and research have an enormous impact on the breakthroughs that help make our visions for a better future a reality.”

For Linda Trinh, that means exploring how exercise can manage the cognitive health of cancer survivors, who often experience impairments in memory, information processing and executive functioning long after their treatment has ended.

“There has been research, especially in aging literature with healthy adults, which shows positive effects of exercise for increasing cognitive function,” says Trinh, an assistant professor of exercise and cancer survivorship at the Faculty of Kinesiology & Physical Education.

“We’re hoping this might apply to cancer survivors and patients as well, given that cognitive impairment is largely underdiagnosed and there are no proven treatments beyond symptom management.”

The award will enable Trinh’s Exercise Oncology Lab to expand its work on exercise-based strategies to support the long-term health and well-being of cancer survivors.

At �鶹ֱ��app Scarborough, Oleksandr Voznyy is focusing his efforts on developing next-generation technologies for low-cost, large-scale storage of renewable energy.

Voznyy’s funding will support his Clean Energy Lab’s high-throughput design, synthesis and testing of novel materials that could facilitate an affordable transition towards cleaner energy.

“It was recently calculated that the cost of energy storage needs to go down by 10 times in order for us to be able to completely switch to renewable energy,” says Voznyy, an assistant professor of chemistry in the department of physical and environmental sciences.

His lab incorporates machine learning to optimize experimental design, allowing for on-the-fly learning with fewer experiments.

“Machine learning is making the high-throughput smarter, and not just by brute-forcing it,” says Voznyy.

“Really, it’s like high-throughput on steroids.”

Laura Niemi’s CFI award will go towards studying how morality unfolds in language and thought, and how this connects to behaviour on the global stage.

“I believe that research that investigates the psychology behind social conflict and diverse moral values can help us figure out practical solutions to conflict,” says Niemi, an assistant professor at the Trudeau Centre for Peace, Conflict and Justice at the Munk School of Global Affairs & Public Policy.

Niemi’s Applied Moral Psychology Lab maintains a dual focus, investigating an array of basic concepts in moral and social psychology while exploring how these topics manifest in the real world.

“On one level, we want to understand the basic science of moral psychology … that’s the part that deals with detailing patterns in language and cognition, and how they relate to people having these diverse moral values,” says Niemi.

“The other leg of the lab is focused on how we can apply these findings to things people care about such as pro-sociality, charitable giving and violence.”

Here’s the full list of 32 �鶹ֱ��app experts who have received funding from the Canada Foundation of Innovation's John R. Evans Leaders Fund:

Andrew Advani, department of medicine and St. Michael’s Hospital: Exploration of pathophysiological mechanisms underlying diabetes and its related complications

Joyce Chen, Faculty of Kinesiology & Physical Education and Sunnybrook Hospital: Optimizing motor learning through music-based behavioural interventions

Sarah Crome, department of immunology and Toronto General Hospital: Harnessing regulatory immune cells to promote transplantation tolerance

Carolyn Cummins, Leslie Dan Faculty of Pharmacy: Regulation of whole-body metabolism by nuclear hormone receptors

Michael Garton, Institute of Biomaterials and Biomedical Engineering: Expanding cell capabilities to sense their environment for therapeutic applications

Sergio Grinstein, department of biochemistry and the Hospital for Sick Children: Investigation of organelle dynamics and remodeling using lattice light-sheet microscopy

Frank Gu, department of chemical engineering and applied chemistry: Automation and intelligent design of nanostructured materials

Shane Harding, department of medical biophysics and Princess Margaret Cancer Centre: DNA damage and cellular physiology: rewiring for a cure

Tony Harris, department of cell and systems biology: Spinning disk confocal microscope to probe molecular networks of cell and tissue morphogenesis

Boris Hinz, Faculty of Dentistry: Slide scanner system to study and develop novel diagnostic tools for oral fibrosis and cancer

Rama Khokha, department of medical biophysics and Princess Margaret Cancer Centre: Developing new interventions for breast and lung cancer

Patrick Lee, department of mechanical and industrial engineering: Multi-material characterization system for developing and testing micro-/nano-layered composites and foams

Fa-Hsuan Lin, department of medical biophysics and Sunnybrook Hospital: Multi-modal functional brain technology

Xinyu Liu, department of mechanical and industrial engineering: Infrastructure for advanced microfluidic nanobiosensing

Philipp Maass, department of molecular genetics and the Hospital for Sick Children: Live-cell imaging of inter-chromosomal contacts by confocal super-resolution microscopy

Andreas Mandelis, department of mechanical and industrial engineering: Facility for advanced non-destructive testing/imaging instrumentation development

Rebecca Neel, department of psychology: A functional approach to stigmatization, motivation, and social judgment

Peter Newman, Factor-Inwentash Faculty of Social Work: MFARR-Asia computer-assisted survey interview and participatory video production lab

Laura Niemi, Munk School of Global Affairs & Public Policy: Moral psychology and global affairs

Justin Nodwell, department of biochemistry: Platform for antibiotic discovery and investigation

Deborah O’Connor, department of nutritional sciences and the Hospital for Sick Children: Maximizing milk in a changing food environment

Alison Olechowski, department of mechanical and industrial engineering: Design Observation Studio

Stephanie Protze, department of molecular genetics and McEwen Stem Cell Institute: Generation of stem cell-derived pacemaker cells for biological pacemaker applications

Amy Ramsey, department of pharmacology and toxicology: Study of disease-causing mutations in NMDA receptor genes

Jessica Sommerville, department of psychology: The origins of social learning and behaviour

Yu Sun, department of mechanical and industrial engineering: Infrastructure for image-guided magnetic micromanipulation of cells and tissues

Margot Taylor, departments of medical imaging, paediatrics, psychology and the Hospital for Sick Children: It’s all about time: Optimising infrastructure for functional brain imaging in children

Linda Trinh, Faculty of Kinesiology & Physical Education: Exercise Oncology and Cognition Lab

Neil Vasdev, department of psychiatry and Centre for Addiction and Mental Health: Automated apparatus for PET radiopharmaceuticals to image the living human brain

Oleksandr Voznyy, department of physical and environmental sciences, �鶹ֱ��app Scarborough: High-throughput facility for design, synthesis and characterization of novel materials for large-scale energy storage

Kaley Walker, department of physics: Measurements of atmospheric gases using a deployable infrared interferometer

Scott Yuzwa, department of laboratory medicine and pathobiology: Extrinsic control of neural precursor cells: molecular mechanisms of brain development and repair

Good news for smokers trying to quit, says �鶹ֱ��app researcher

lavende4 — Mon, 25 Apr 2016 14:46:28 +0000

Good news for smokers trying to quit, says �鶹ֱ��app researcher lavende4 Mon, 04/25/2016 - 10:46

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Laurie Zawertailo

Heidi Singer

Author legacy

Heidi Singer

Topic

Centre for Addiction and Mental Health

There’s good news for smokers trying to kick the habit: several smoking cessation medications don’t appear to increase the incidence of serious neuropsychiatric side effects compared to placebo, according to a study published in The Lancet on April 22.

The study, involving 8,000 people, is the largest trial to date looking at the safety and efficacy of three first-line smoking cessation treatments – varenicline, bupropion and nicotine patches – compared to placebo in smokers with and without psychiatric disorders. As well, the authors found varenicline had the highest success rate among the three medications.

“This is the latest reassuring study showing no link between smoking-cessation medications and neuropsychiatric symptoms, such as suicidal ideation, depression and panic,” says Laurie Zawertailo, an assistant professor in the department of pharmacology and toxicology at the University of Toronto. “This suggests that health providers should be comfortable prescribing smoking-cessation medication without worry about specific medications causing neuro-psychiatric side effects.”

Zawertailo, who is also a tobacco dependence researcher with the Centre for Addiction and Mental Health, wrote an accompanying Comment linked to the study.

In that piece, she also cautioned that caregivers should make people aware that quitting smoking – regardless of the method used – does create a small increased risk of severe changes to mood and psychiatric well-being.

Participants in the study were adults aged 18-75 who smoked on average more than 10 cigarettes a day and were motivated to stop smoking. Half had a history of a past or current stable psychiatric condition including a mood, anxiety, psychotic, or borderline personality disorder, and about half of this group were taking psychotropic medication.

For smokers without a psychiatric disorder, there was no significant increase in the incidence of adverse neuropsychiatric events across the four treatment groups.

Overall, there were more adverse neuropsychiatric events reported in the group with psychiatric disorders (4.9-6.7%) than in the group without (1.3-2.5%). However, the researchers found there were similar rates among the three treatments studied (6.5% varenicline; 6.7% bupropion; 5.2% nicotine patch; 4.9% placebo).

Varenicline was more effective in helping people stop smoking than bupropion, nicotine patches, or placebo. Bupropion was about as effective as nicotine patches, and both were more effective than placebo. Overall, at 9-24 weeks, 21.8% of people on varenicline hadn’t smoked, while this rate was 16.2% for bupropion and 15.7% for nicotine patches. Smokers with a psychiatric disorder achieved slightly lower abstinence rates than smokers without a psychiatric disorder.

The authors warn that since the participants had a stable psychiatric disorder and were being treated, the findings might not apply to those with untreated or unstable psychiatric illness. The researchers also excluded people with current alcohol or substance abuse disorders and people who were at imminent risk of suicide. The study also did not look at whether the strength of nicotine dependence, or the severity of psychiatric symptoms, affected the findings. Finally, just over 20% of people dropped out of the study but this was seen across the board, whether or not participants had a psychiatric disorder and irrespective of whether they received one of the three treatments or placebo.

“Quitting smoking is difficult but can be made easier with medication and counselling,” says Zawertailo. “With these promising results from the largest study to date, clinicians and patients can now have more confidence in the safety and effectiveness of the three available pharmacotherapies for smoking cessation.”