PRiME

Support for HI³ and the four funded research programs through the CBRF and BRIF is part of a larger investment in Canada’s Biomanufacturing and Life Sciences Strategy. The strategy aims to grow a strong, competitive domestic life sciences sector with cutting-edge biomanufacturing capabilities and to improve the country’s ability to respond to future health challenges.

HI³ – a coalition of 87 academic, hospital, research networks, industry, government, not-for-profit and community partners – was one of five national hubs established in March 2023 with CBRF funding.

Together, the four awarded programs will provide critical health intelligence data to guide the co-development of health threat surveillance platforms and next-generation precision interventions by the hub’s academic and industry partners, while building a highly skilled workforce to support Canada’s growing biomanufacturing and life sciences sector.

“Congratulations to HI³ and the collaborative teams behind these CBRF-funded programs. These four programs leverage the tremendous expertise of the �ؿ�ζSM's researchers and our partners in academia, hospitals, industry and other sectors to develop the talent, tools and data required to be at the forefront of emerging health threats,” said Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives.

“On behalf of the �ؿ�ζSM and HI³, I thank the government of Canada for its investment in building a strong domestic life sciences sector ready to take on the health challenges of today and tomorrow.”

One of the CBRF-funded programs is the Biomanufacturing Hub Network (BioHubNet), an immersive talent development program based at U of T and led by University Professor Molly Shoichet along with Darius Rackus, an assistant professor of chemistry and biology at Toronto Metropolitan University, and Gilbert Walker, a professor of chemistry at U of T.

“With world-leading scientists and researchers established across Canadian leading research institutions, Canada is home to a competitive and robust biomanufacturing and life sciences sector. We made a promise to Canadians that we would rebuild the domestic sector,” said François-Philippe Champagne, Canada’s minister of innovation, science and industry. “With this investment, our government is delivering on this promise by supporting the excellent innovations, collaborations and infrastructures necessary to rapidly respond to future public health threats and keep Canadians safe.”

The predicted supply of biomanufacturing workers is only enough to fill one-quarter of the positions that will be needed in the sector by 2029, according to a 2021 report from BioTalent Canada.

To address the shortage, BioHubNet will leverage its 26 industry and training partners – which include multinational and homegrown biotechnology companies, as well as five Ontario colleges and nearly $19 million in funding from CBRF – to develop a range of training programs and curricula that provide experiential, hands-on learning to graduate students, postdoctoral fellows and others who are ready to transition to industry.

The program will also outfit entrepreneurs with the skills and resources they need to commercialize their lab-based innovations, further strengthening the translational pipeline. Over the next four years, BioHubNet will produce close to 1,000 highly skilled workers through micro-credential courses, industry internships, academic exchange placements and entrepreneurial training.

A central tenet underlying all BioHubNet’s offerings is a commitment to create more equitable and inclusive participation in the biomanufacturing and life sciences sectors through intentional recruitment and active support for trainees from under-represented groups.

“Canada’s future as a leader in bio-innovation depends on having highly qualified workers, yet the sector is predicted to face severe workforce shortages in the coming years,” says Shoichet, who is the Michael E Charles Professor in Chemical Engineering at U of T and scientific director of PRiME Next-Generation Precision Medicine, a U of T institutional strategic initiative based at the Leslie Dan Faculty of Pharmacy.

“By expanding the pipeline of skilled research talent in Canada, BioHubNet will accelerate the translation of promising discoveries from bench to market and ensure that this country’s biomanufacturing sector continues to grow and attract further international investment.”

In addition to BioHubNet, three other research programs were also funded:

The Integrated Network for the Surveillance of Pathogens: Increasing Resilience and capacity in Canada’s pandemic response (INSPIRE) based at the University of Windsor. Co-led by Windsor professor Mike McKay and University of Guelph professor Lawrence Goodridge, the INSPIRE program leverages community-level wastewater surveillance data, infrastructure and expertise to monitor the arrival and spread of infectious threats. The program also received infrastructure funding from BRIF to implement technologies and processes across its network that will streamline wastewater surveillance efforts to be more rapid, agile and sensitive. Importantly, these infrastructure supports will expand wastewater monitoring capacity in northern Ontario and at the Windsor-Detroit border to strengthen supply chains.
The Prepare, React, Collect, Innovate, Share and Engage (PRECISE) Diagnostic Platform, based at Sinai Health and co-led by Jennie Johnstone and Anne-Claude Gingras – who are both faculty members in U of T’s Faculty of Medicine – will advance a comprehensive, streamlined approach for responding to emerging threats by driving the timely development of rapid diagnostic tools that will scale up testing capacity and reduce reliance on global supply chains.
The Pandemic Preparedness Engaging Primary Care and Emergency Departments (PREPARED) program, based at Unity Health Toronto and led by Andrew Pinto, who is a faculty member in the Temerty Faculty of Medicine, aims to engage primary care clinics and emergency departments across the country to enhance disease monitoring, improve patient care and health system efficiency, accelerate the development of medical countermeasures and boost recruitment to clinical trials.

All four research programs reflect the hub’s extensive network of nearly 100 partners from academia, hospital, industry, public and other sectors. The programs leverage the collective resources and expertise of this network, including U of T’s position as a global leader in artificial intelligence, data, life sciences and engineering, and the Toronto Academic Health Sciences Network’s strong track record of clinical impact and health-care innovation.

“Our goal at HI³ is to advance mission-driven, team-based science that will help Canada be more prepared, resilient and independent in the face of emerging health threats,” said Jen Gommerman, co-director of HI³ and a professor of immunology in U of T’s Temerty Faculty of Medicine.

“As we support and grow these four research programs, we will continue to work closely with our hub partners and with our counterparts across the country to ensure that we have the capacity and resources needed to respond in a co-ordinated, effective and equitable manner.”

Researchers discover lipid nanoparticle that delivers mRNA to muscles, avoids other tissues

Christopher.Sorensen — Fri, 15 Dec 2023 20:01:28 +0000

Researchers discover lipid nanoparticle that delivers mRNA to muscles, avoids other tissues

Christopher.Sorensen Fri, 12/15/2023 - 15:01

Cutline

“The substantial anti-tumor effects observed with iso-A11B5C1 underscore its promise as a viable candidate for cancer vaccine development,” says Jingan Chen, a PhD trainee from the Institute of Biomedical Engineering (photo by Steve Southon)

Kate Richards

Topic

Breaking Research

Institute of Biomedical Engineering

Institutional Strategic Initiatives

PRiME

Cancer

Graduate Students

Leslie Dan Faculty of Pharmacy

Research & Innovation

Vaccines

Subheadline

Study also showed the mRNA triggered potent cellular-level immune responses, suggesting it could be used to develop a melanoma cancer vaccine

A team of researchers based at the �ؿ�ζSM’s Leslie Dan Faculty of Pharmacy have discovered an ionizable lipid nanoparticle that delivers mRNA to muscles while avoiding other tissues.

The study, led by Assistant Professor Bowen Li and published in Proceedings of the National Academy of Sciences, also showed that mRNA delivered using the lipid nanoparticles triggered potent cellular-level immune responses – a proof-of-concept that could lead to a potential melanoma cancer vaccine.

Called iso-A11B5C1, the new lipid nanoparticle demonstrates exceptional mRNA delivery efficiency in muscle tissues while also minimizing unintended mRNA translation in organs such as the liver and spleen. Additionally, study results show that intramuscular administration of mRNA formulated with this nanoparticle caused potent cellular immune responses, even with limited expression observed in lymph nodes.

“Our study showcases for the first time that mRNA lipid nanoparticles can still effectively stimulate a cellular immune response and produce robust anti-tumor effects, even without direct targeting or transfecting lymph nodes,” said Li.

“This finding challenges conventional understandings and suggests that high transfection efficiency in immune cells may not be the only path to developing effective mRNA vaccines for cancer.”

Lipid nanoparticles, also called LNPs, are crucial for delivering mRNA-based therapies including COVID-19 mRNA vaccines that were used worldwide during the recent pandemic. However, many LNP designs can inadvertently result in substantial mRNA expression in off-target tissues and organs like the liver or heart, resulting in often treatable but unwanted side effects. The drive to improve the safety of mRNA therapies that have the potential to treat a broad range of diseases means there is an urgent need for LNPs designed to minimize these off-target effects, explains Li, a recent recipient of the Gairdner Early Career Investigator Award.

From left to right: researchers Jingan Chen, Bowen Li and Yue Xu (photo by Steve Southon)

The new research shows that, compared to the current benchmark LNP developed by the Massachusetts-based biotechnology company Moderna, iso-A11B5C1 demonstrated a high level of muscle-specific mRNA delivery efficiency. It also triggered a different kind of immune response than what is seen in vaccines used to treat infectious diseases.

“Interestingly, iso-A11B5C1 triggered a lower humoral immune response, typically central to current antibody-focused vaccines, but still elicited a comparable cellular immune response. This finding led our team to further explore this as a potential cancer vaccine candidate in a melanoma model, where cellular immunity plays a pivotal role,” Li said.

The interdisciplinary research team that conducted the study includes Jingan Chen, a PhD trainee from the Institute of Biomedical Engineering, and Yue Xu, a postdoctoral researcher in the Li lab and a research fellow associated with PRiME, a U of T institutional strategic initiative.

“Although iso-A11B5C1 showed limited capacity to trigger humoral immunity, it effectively initiated cellular immune responses through intramuscular injection,” said Chen. “The substantial anti-tumor effects observed with iso-A11B5C1 underscore its promise as a viable candidate for cancer vaccine development.”

New platform allows for faster, more precise lipid design

The research team identified iso-A11B5C1 by using an advanced platform developed to quickly create a range of chemically diverse lipids for further testing. This platform, newly introduced as part of the study, overcomes several challenges by streamlining the process of creating ionizable lipids that have a high potential to be translated into therapies.

By rapidly combining three different functional groups, hundreds to thousands of chemically diverse ionizable lipids can be synthesized within 12 hours.

“Here we report a powerful strategy to synthesize ionizable liquids in a one-step chemical reaction,” said Xu. “This new platform provides new insights that could help guide lipid design and evaluation processes going forward and allows the field to tackle challenges in RNA delivery with a new level of speed, precision and insight.”

Molly Shoichet named director of U of T's precision medicine initiative

Christopher.Sorensen — Fri, 25 Aug 2023 13:09:13 +0000

Molly Shoichet named director of U of T's precision medicine initiative

Christopher.Sorensen Fri, 08/25/2023 - 09:09

Cutline

Molly Shoichet (photo by Steve Southon)

Kate Richards

Topic

Our Community

Institutional Strategic Initiatives

PRiME

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Research & Innovation

Subheadline

"It’s crucial that we address not just the complexity of disease but how we can diagnose and do a better job delivering these new treatments to patients”

Molly Shoichet has been named scientific director of the �ؿ�ζSM’s PRiME Next-Generation Precision Medicine – an institutional strategic initiative that tackles unmet needs in drug discovery, diagnostics and disease biology.

Based at the Leslie Dan Faculty of Pharmacy, PRiME brings together multi-disciplinary research talent and innovators to act as an accelerator for precision medicine.

“It is such an exciting time in precision medicine,” says Shoichet, a University Professor in the Faculty of Applied Science & Engineering with a cross appointment to the Leslie Dan Faculty of Pharmacy who is the Michael E Charles Professor of Chemical Engineering. “We know that a one size fits all approach doesn’t work well in medicine. We can now take advantage of advances in ’omics’ – genomics, metabolomics, proteomics – AI, and engineered materials to design therapeutics more precisely for individual needs.

“From a research and translation perspective, it’s crucial that we address not just the complexity of disease but how we can diagnose and do a better job delivering these new treatments to patients.”

Since launching in 2019, PRiME has grown to include more than 90 faculty from 16 departments across U of T’s three campuses, with more than 200 graduate trainees connected to the initiative.

Under the leadership of Shoichet, PRiME will focus on expanding translation of research advances through collaboration with U of T’s partner hospitals and industry colleagues, growing PRiME into a hub to enable researchers to develop new solutions to key clinical challenges.

“U of T is a powerhouse in biomedical research that is recognized throughout the world,” says Shoichet. “This is strengthened not only by researchers in fields like pharmacy and engineering, but by being part of a broad ecosystem that is uniquely poised to accelerate new solutions for unmet needs in human disease. PRiME brings the diversity of ideas into solutions-focused, multidisciplinary research that will help us move the needle.”

For example, Shoichet and fellow PRiME principal investigator Stéphane Angers, a professor in the Temerty Faculty of Medicine and the Donnelly Centre for Cellular and Biomolecular Research, are collaborating with SickKids Senior Scientist Peter Dirks, who is also a professor in the Temerty Faculty of Medicine, to tackle glioblastoma – the deadliest primary tumour for which there are no therapies.

Working with commercialization partner TIAP (Toronto Innovation Acceleration Partners) and industry partner Amgen, PRiME scientists are identifying new therapeutic targets for glioblastoma by combining their expertise in gene editing and specifically designed hydrogels.

Patient-derived glioblastoma stem cells invade into a biomimetic hydrogel (supplied image)

Shoichet is known internationally for innovative research in drug delivery, drug discovery and hydrogels. Materials and techniques invented by Shoichet and her team aim to both promote tissue repair in the brain and spinal cord and discover new drugs in cancer. An Officer of the Order of Canada and Fellow of the Royal Society (UK), Shoichet was awarded Canada’s most prestigious award for science and engineering in 2020 - the Gerhard Herzberg Canada Gold Medal for Science.

Carolyn Cummins, Associate Professor in the department of pharmaceutical sciences at the Leslie Dan Faculty of Pharmacy and the Associate Scientific Director of PRiME (photo by Steve Southon)

“The Toronto biotech ecosystem is thriving,” says Carolyn Cummins, an associate professor in the department of pharmaceutical sciences aint the Leslie Dan Faculty of Pharmacy and the associate scientific director of PRiME. “I am excited to work closely with Professor Shoichet to deliver the potential of PRiME at this pivotal time.”

In the coming months, PRiME will launch new programs and events for principal investigators and trainees to build inter-disciplinary and translational collaborations. This includes the new PRiME Inter-Disciplinary Catalyst Program and Fellowships in fall 2023, with partners from across the Toronto drug discovery community.

Researchers shrink brain tumours with gold nanoparticles, develop ‘mini brains’ to study psychiatric disorders

Christopher.Sorensen — Tue, 18 Oct 2022 14:03:07 +0000

Researchers shrink brain tumours with gold nanoparticles, develop ‘mini brains’ to study psychiatric disorders

Christopher.Sorensen Tue, 10/18/2022 - 10:03

Cutline

(Photo by Aja Koska/Getty Images)

Tina Adamopoulos

Topic

Our Community

Groundbreakers

Institutional Strategic Initiatives

PRiME

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Chemistry

Faculty of Arts & Science

Graduate Students

Leslie Dan Faculty of Pharmacy

Medicine by Design

Researchers at the �ؿ�ζSM are inching closer to realizing a life-saving brain cancer treatment by using gold nanoparticles to make radiation therapy more effective and less toxic for patients.

In their battle against glioblastoma multiforme (GBM), a rare, fast-growing cancer that begins in the brain, the multidisciplinary team has discovered that the nanoparticles can keep radiation tightly focused on the tumour, shrinking its size and preventing damage elsewhere in the body.

Only a handful of researchers around the world are focused on radiolabeled nanoparticle research for brain tumours.

Raymond Reilly

“There is a small group of scientists working on radiation nanomedicines globally – and an even smaller group studying the therapeutic use of radiolabeled gold nanoparticles,” says Raymond Reilly, a renowned specialist in radiopharmaceuticals and professor in the Leslie Dan Faculty of Pharmacy who is supervising the team.

“To my knowledge, we're one of the few groups in the world that have studied local infusion of radiolabeled gold nanoparticles for treatment of brain tumours.”

Anchoring radioisotopes in the brain

In animal studies, the use of gold nanoparticles in radiation resulted in tumours that were no longer detectable by MRI four weeks after the treatment. The researchers also found evidence of prolonged survival – and a potential cure – following the 150-day trial.

Constantine Georgiou

“We use gold nanoparticles to hold the radiation, or radioisotope, where we inject it into the brain,” says Constantine Georgiou, a graduate student in the department of pharmaceutical studies who works with Reilly.

“Without the gold nanoparticle, the radiation leaves the brain tumour, making it non-effective.”

The radiation also effectively erased tumour cells without causing any apparent damage to the brain or other tissues in the body – travelling no more than two millimetres from the site of injection. In other words, there appears to be no toxicity associated with the treatment.

To evaluate the effectiveness of the therapy, Georgiou used innovative imaging techniques such as single-photon emission computed tomography (SPECT) imaging, a type of nuclear medicine imaging that allows researchers to visualize where the gold nanoparticles are located in the brain, and bioluminescence and MRI imaging to track the growth of the tumour.

The project was first developed under Noor Al-saden, one of 10 trainees at U of T who took part in the inaugural 2019 PRiME Fellowship Awards – a program to propel high-risk, high-reward, multidisciplinary research in precision medicine. PRiME is an Institutional Strategic Initiative (ISI) at U of T that connects scientists, engineers and other innovators across different disciplines to accelerate drug discovery, diagnostics and understanding of disease biology.

Preliminary results from Al-saden’s PRiME research and a seed grant from the Brain Tumour Foundation of Canada helped Reilly’s group secure a $200,000 Canadian Cancer Society Innovation Grant.

The development of radiation nanomedicine requires a multidisciplinary approach.

At U of T, the research would not have been possible without the expertise of world-renowned polymer chemist Mitch Winnik, a professor in the department of chemistry in Faculty of Arts & Science. That’s because the radioisotope – in this case, Lutetium-177 – is attached to gold nanoparticles by a polymer synthesised by Winnik’s group, a substance made of large molecules with various metal-binding sites.

The team’s next research phase will take place in a new space at U of T: the Good Manufacturing Practices (GMP) facility in the Leslie Dan Faculty of Pharmacy. Made possible by a $1.3 million grant awarded to Reilly from the Canadian Foundation for Innovation and Ontario Research Fund, the facility was launched earlier this year to create radiopharmaceuticals for clinical trials.

Georgiou and Reilly are currently studying radiation nanomedicine combined with immunotherapy to provide a more durable tumour response to treat GBM. The group also plans to study the effectiveness of other radioisotopes attached to the gold nanoparticles, which may achieve even more precision in erasing cancer cells.

A deeper understanding of energy metabolism in brain disorders by making ‘mini brains’

Reilly and Georgiou’s research isn’t the only innovative, brain-focused project that’s being supported by PRiME.

Angela Duong

Research by Angela Duong, a U of T alumna and a 2019 PRiME fellow, developed 2D and 3D brain models from patients to gain insights into the role that mitochondrial function plays in neuronal activity – specifically in patients with bipolar disorder.

Working alongside Ana Cristina Andreazza – a professor in the departments of pharmacology and toxicology and psychiatry in the Temerty Faculty of Medicine, with a cross appointment at the Centre for Addiction and Mental Health – Duong built 3D in vitro cultures of brain cells, also known as cerebral organoids, to identify biological targets that can be used to guide the development of therapeutics. In doing so, Duong overcame longstanding hurdles in understanding the biology of patients with psychiatric disorders since researchers previously relied on two limited avenues for investigation: post-mortem brain samples, which are scarce, and brain imaging technologies which are expensive and may require radioactive exposure.

Duong describes her cerebral organoids as “mini brains” that retain patient genetic background, allowing researchers to study human-specific processes that might be related to the clinical diagnosis of the patients. She says this tool is useful for disease modelling compared to brain samples from animals which do not carry the complex human genes that cause psychiatric disorders.

“In the brain, 20 per cent of our body’s total energy budget is used to support neurotransmission. This is a very energy-demanding process that allows brain cells to communicate with each other, Duong says. “So, if there is metabolic dysfunction in the brain, the process of neurotransmission is also affected, which we think is related to the symptoms and mood changes that we commonly see in patients with psychiatric disorders.”

“By developing 'mini brains' to function as disease models, we can learn what metabolic changes are going on in the brain of actual patients with brain diseases without invasive brain biopsies or studying the brains of mice or rats."

To do this, Duong collected blood samples from patients with and without bipolar disorder and isolated their white blood cells. The cells were then reprogrammed into induced pluripotent stem cells (iPSCs), a stem cell that can be generated directly from a somatic cell, any cell of a living organism other than reproductive ones. Using these iPSCs, Duong later created 2D and 3D brain cells, or organoids.

Duong’s project was among the first to fully characterize the brain’s mitochondrial health, from white blood cells to iPSCs to cerebral organoids. That, in turn, offered validation about whether mitochondria stay healthy throughout the reprogramming and differentiation process. This study provides important groundwork for creating more sophisticated patient 2D and 3D brain cells for disease modelling and the study of mitochondrial dysfunction across a wide range of brain diseases.

The achievement required the multidisciplinary collaboration of three different U of T labs.

Liliana Attisano

In addition to Andreazza’s lab, the PRiME project brought in expertise from two professors at the Temerty Faculty of Medicine to work on the 3D engineered organoids: Liliana Attisano, a professor of biochemistry in the Temerty Faculty of Medicine and at the Donnelly Centre for Cellular and Biomolecular Research, and Martin Beaulieu, an associate professor in the department of pharmacology and toxicology in the Temerty Faculty of Medicine.

Building self-developing brain cells

Organoid production relies on the cell’s self-organizing properties to develop required cell types.

The goal of Attisano’s lab was to develop protocols to produce cerebral organoids that were all the same size and shape to decrease variability, making it easier for researchers to find the answers to their questions. To accomplish this, researchers added growth factors or inhibitors that moved the cells into a neural lineage. After that, the cells divided and developed for about a month – just as they would in a human brain. The lineage can also be modified to make organoids for other body parts, such as the liver.

Beaulieu’s lab, meanwhile, provided equipment and resources to characterize the electroactivity of the neurons within the organoids.

Duong’s technological model is now being used by Andreazza to further develop cerebral organoids to further investigate a range of psychiatric conditions.

Meanwhile, Attisano is making cerebral organoids available for researchers across Toronto with an organoid production platform called Applied Organoid Core (ApOC), funded by the Brain Canada Foundation’s 2019 Platform Support Grant, and U of T’s Medicine by Design strategic initiative. The ApOC is a $1,425,000 grant. Through this project, Attisano is collaborating with other researchers who want to use cerebral organoids to map human brain development and disorders such as epilepsy.

“When it comes down to it, brain disorders are simply a kind of alteration in molecular components that result in altered behaviour. It’s no different from a mutation that makes you susceptible to cancer. But we never had the capacity to study this,” Attisano says.

“Cerebral organoids give us that potential.”

This article is part of a multimedia series about U of T's Institutional Strategic Initiatives program – which seeks to make life-changing advancements in everything from infectious diseases to social justice – and the research community that's driving it.