Kate Richards

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 University of Toronto’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 University of Toronto’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.

With $3-million chair, U of T and GSK focus on enhancing pharmacist-led vaccine care

Christopher.Sorensen — Wed, 10 May 2023 16:57:15 +0000

With $3-million chair, U of T and GSK focus on enhancing pharmacist-led vaccine care

Christopher.Sorensen Wed, 05/10/2023 - 12:57

Cutline

(photo by Prostock Studio)

Kate Richards

Topic

Our Community

Leslie Dan Faculty of Pharmacy

Research & Innovation

Vaccines

The University of Toronto and biopharma company, GSK are investing a combined $3 million – $2 million from GSK and $1 million from the Leslie Dan Faculty of Pharmacy – to create a new chair that will enhance and develop vaccine education programs and practice tools for pharmacists and other health professionals.

Based at the Leslie Dan Faculty of Pharmacy, the GSK Chair in Vaccine Education and Practice-Oriented Tools will build on current knowledge and training to equip pharmacists with the skills and tools to adapt to the rapidly evolving clinical scope of practice and the needs of patients and communities.

The chair will also develop evidence-based models of vaccine care that build trust, expand access and improve health outcomes.

“Community pharmacies are increasingly seen as health hubs for primary-care services and pharmacists are ideally suited to promote the best health outcomes for vaccine-preventable diseases at all stages, from childhood to older adults,” said Lisa Dolovich, professor and dean at U of T’s Leslie Dan Faculty of Pharmacy. “The support from GSK to establish this chair is vital to advancing our education and research in this important area of practice.”

From left to right: Dr. Bryan Tennant, scientific director, vaccines, GSK Canada; Marni Freeman, vice-president and country medical director, GSK Canada; Peter Fonyodi, business unit head, vaccines, GSK Canada; Jamie Kellar, associate dean, academic, Leslie Dan Faculty of Pharmacy; Emanuela De Franco, national director partnerships and governmental affairs, GSK Canada; and Lisa Dolovich, professor and dean, Leslie Dan Faculty of Pharmacy.

As one of the most accessible primary-care providers, pharmacists engage in health promotion, identify indications for vaccines, provide education to patients, administer vaccines and deliver follow-up care.

“At GSK, we believe strong collaborations, such as this one with U of T, are key to driving innovation and excellence in research and education with the goal of improving patient experiences and health outcomes,” said Dr. Bryan Tennant, scientific director, vaccines, at GSK Canada. “We believe that the Leslie Dan Faculty of Pharmacy and the new GSK Chair in Vaccine Education and Practice-Oriented Tools will lead the way in equipping the next generation of pharmacists for an always evolving world and set new standards in education across Canada and around the globe.”

During the mass rollout of COVID-19 vaccines, pharmacy teams across Canada demonstrated the ability to mobilize to meet public health needs in times of crisis. As the impact of the pandemic continues to stretch our health system, pharmacists are taking on an increased role in primary care, filling care gaps with pharmacy clinic services that include vaccinations. “But we need to ensure pharmacists are continually supported with evidenced-based tools to provide the best possible care over time,” Dolovich said.

As a result of limited access and other barriers brought on during the height of the pandemic, many children and adults are behind on routine immunizations.

A 2022 survey led by Campaign Research showed that one in five Ontario adults missed or delayed their routine immunization for preventable illnesses like shingles and pneumonia. Pharmacy teams can help address gaps in care like this and have demonstrated the ability to be nimble enough to implement new, innovative ways of providing critical health services.

“Further supporting and enhancing the role of pharmacists as vaccine-care providers expands access for patients and helps support the health of our families and communities,” said Dolovich. “The creation of this chair provides an exciting opportunity to focus on how pharmacists can continue to play an important role in managing vaccine-preventable diseases.”

The Leslie Dan Faculty of Pharmacy will soon begin recruitment for the chair through an open call for applications and submissions outlining proposed research programs that will drive the vision and impact of this initiative forward.

U of T scientists use AI to fast-track drug formulation development

siddiq22 — Wed, 11 Jan 2023 20:34:30 +0000

U of T scientists use AI to fast-track drug formulation development

siddiq22 Wed, 01/11/2023 - 15:34

Cutline

Researchers Christine Allen and Alán Aspuru-Guzik used machine learning to predict experimental drug release from long-acting injectables (photo by Steve Southon)

Kate Richards

Topic

Breaking Research

Acceleration Consortium

Artificial Intelligence

Chemistry

Computer Science

Leslie Dan Faculty of Pharmacy

Research & Innovation

In a bid to reduce the time and cost associated with developing promising new medicines, University of Toronto scientists have successfully tested the use of artificial intelligence to guide the design of long-acting injectable drug formulations.

The study, published this week in Nature Communication, was led by Professor Christine Allen in the Leslie Dan Faculty of Pharmacy and Alán Aspuru-Guzik in the departments of chemistry and computer science in the Faculty of Arts & Science.

Their multidisciplinary research shows that machine-learning algorithms can be used to predict experimental drug release from long-acting injectables (LAI) and can also help guide the design of new LAIs.

“This study takes a critical step towards data-driven drug formulation development with an emphasis on long-acting injectables,” said Allen, who is a member of U of T's Acceleration Consortium, a global initiative that uses artificial intelligence and automation to accelerate the discovery of materials and molecules needed for a sustainable future.

“We’ve seen how machine learning has enabled incredible leap-step advances in the discovery of new molecules that have the potential to become medicines. We are now working to apply the same techniques to help us design better drug formulations and, ultimately, better medicines.”

Considered one of the most promising therapeutic strategies for the treatment of chronic diseases, long-acting injectables are a class of advanced drug delivery systems that are designed to release their cargo over extended periods of time to achieve a prolonged therapeutic effect. This approach can help patients better adhere to their medication regimen, reduce side effects and increase efficacy when injected close to the site of action in the body.

However, achieving the optimal amount of drug release over the desired period of time requires the development of a wide array of formulation candidates through extensive and time-consuming experiments. This trial-and-error approach has created a significant bottleneck in LAI development compared to more conventional types of drug formulation.

“AI is transforming the way we do science. It helps accelerate discovery and optimization. This is a perfect example of a ‘before AI’ and an ‘after AI’ moment and shows how drug delivery can be impacted by this multidisciplinary research,” said Aspuru-Guzik, who is director of the Acceleration Consortium and holds the CIFAR Artificial Intelligence Research Chair at the Vector Institute in Toronto and the Canada 150 Research Chair in Theoretical and Quantum Chemistry.

From left: Zeqing Bao, PhD trainee in pharmaceutical sciences, and Riley Hickman, PhD trainee in chemistry, are co-authors on the study published in Nature Communication (photo by Steve Southon)

Reducing ‘trial and error’ for new drug development

To investigate whether machine-learning tools could accurately predict the rate of drug release, the research team trained and evaluated a series of 11 different models, including multiple linear regression (MLR), random forest (RF), light gradient boosting machine (lightGBM) and neural networks (NN). The data set used to train the selected panel of machine learning models was constructed from previously published studies by the authors and other research groups.

“Once we had the data set, we split it into two subsets: one used for training the models and one for testing,” said Pauric Bannigan, research associate with the Allen research group at the Leslie Dan Faculty of Pharmacy. “We then asked the models to predict the results of the test set and directly compared with previous experimental data. We found that the tree-based models, and specifically lightGBM, delivered the most accurate predictions."

As a next step, the team worked to apply these predictions and illustrate how machine learning models might be used to inform the design of new LAIs by using advanced analytical techniques to extract design criteria from the lightGBM model. This allowed the design of a new LAI formulation for a drug currently used to treat ovarian cancer.

Expectations around the speed with which new drug formulations are developed have heightened drastically since the onset of the COVID-19 pandemic.

“We’ve seen in the pandemic that there was a need to design a new formulation in weeks, to catch up with evolving variants. Allowing for new formulations to be developed in a short period of time, relative to what has been done in the past using conventional methods, is crucially important so that patients can benefit from new therapies,” Allen said, explaining that the research team is also investigating using machine learning to support the development of novel mRNA and lipid nanoparticle formulations.

More robust databases needed for future advances

The results of the current study signal the potential for machine learning to reduce reliance on trial-and-error testing. However, Allen and the research team identify that the lack of available open-source data sets in pharmaceutical sciences represents a significant challenge to future progress.

“When we began this project, we were surprised by the lack of data reported across numerous studies using polymeric microparticles,” Allen said. “This meant the studies and the work that went into them couldn’t be leveraged to develop the machine learning models we need to propel advances in this space. There is a real need to create robust databases in pharmaceutical sciences that are open access and available for all so that we can work together to advance the field."

To that end, Allen and the research team have published their datasets and code on the open-source platform Zenodo.

“For this study our goal was to lower the barrier of entry to applying machine learning in pharmaceutical sciences,” Bannigan said. “We’ve made our data sets fully available so others can hopefully build on this work. We want this to be the start of something and not the end of the story for machine learning in drug formulation.”

The study was supported by the Natural Sciences and Engineering Research Council of Canada, the Defense Advance Research Projects Agency and the Vector Institute.

U of T pharmacy and public health faculties partner to strengthen pharmacists’ role in health system

Christopher.Sorensen — Tue, 22 Nov 2022 14:16:48 +0000

U of T pharmacy and public health faculties partner to strengthen pharmacists’ role in health system

Christopher.Sorensen Tue, 11/22/2022 - 09:16

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Adalsteinn Brown, dean of the Dalla Lana School of Public Health, and Lisa Dolovich, dean of the Leslie Dan Faculty of Pharmacy, are collaborating with Shoppers Drug Mart to find ways to improve Canada's health system (photo by Polina Teif)

Kate Richards

Topic

Our Community

Dalla Lana School of Public Health

Health

Leslie Dan Faculty of Pharmacy

Research & Innovation

The University of Toronto’s Leslie Dan Faculty of Pharmacy and Dalla Lana School of Public Health, along with Shoppers Drug Mart, have announced a new collaboration to study how pharmacists can better support Canada’s overburdened health system.

The research will review and evaluate what the expanded role for pharmacists might achieve, and how pharmacy teams can help improve access to care in communities.

Supported by a $3-million donation from Shoppers Drug Mart, the collaboration will create a strong engine for evidence and knowledge transfer around pharmacy practice, health policy, data science and improved patient care, said Professor Lisa Dolovich, dean of the Leslie Dan Faculty of Pharmacy and an expert in health systems research.

“Pharmacy teams reach more people daily than any other part of our health system. We are very excited about this partnership and the potential for pharmacy and public health experts to deliver viable and sustainable solutions for our health system that is currently experiencing incredible strain,” Dolovich said. “The COVID-19 pandemic brought significant challenges, but it also demonstrated the power of increased collaboration across health care. This donation provides resources needed to build on that experience and further strengthen the role of pharmacists to help meet patient needs in the community.”

The donation will support: research projects aimed at understanding the expanding role of pharmacists and how a more integrated health system can connect and leverage care in pharmacies; scholarships for students at both faculties working in the areas of pharmacy, health system improvement and other relevant issues; and real world testing and evaluation projects to be led in collaboration with the recently launched Discovery Pharmacy, based at the Leslie Dan Faculty of Pharmacy.

"To make our health systems more effective and resilient, we must enable each health professional to fully deploy their skills and expertise,” said Professor Adalsteinn Brown, dean of the Dalla Lana School of Public Health. “With this exciting partnership, public health and health systems researchers will help to alleviate critical gaps in our public health and primary care systems.”

This collaborative opportunity leverages the potential for research, innovation, and policy to address pressing public health issues and improve community-based, patient-centered care. Promising solutions and innovations will be developed, evaluated, and shared with academic and health system partners through formal knowledge mobilization efforts.

“The Canadian healthcare system is plagued by a number of complex issues, all of which require innovation and collaboration to overcome,” said Jeff Leger, president of Shoppers Drug Mart. “We believe pharmacists can play a vital role in a collective solution and are pleased to be partnering with the University of Toronto as they continue their work to ensure the pharmacists of the future are equipped to meet society’s ever evolving health care needs.”

In addition to creating solutions to improve access to community-based care, a key area of focus for this initiative is to examine and expand the use of population-level digital tools to help guide patients and their care providers to identify problems before they arise, recognize opportunities to better manage chronic conditions and generate evidence on how to develop new tailored ways of delivering health care.

“Sustainable, integrated and technology-enabled solutions in health care and public health are realistic and achievable,” said Dolovich. “Our efforts will support and improve the health of Canadians and the quality of our health system.”

Experts create tool to help doctors avoid prescribing drugs to treat other drugs’ side effects

Christopher.Sorensen — Tue, 20 Sep 2022 17:14:57 +0000

Experts create tool to help doctors avoid prescribing drugs to treat other drugs’ side effects

Christopher.Sorensen Tue, 09/20/2022 - 13:14

Cutline

Experts atU of T’s Leslie Dan Faculty of Pharmacy and Women’s College Hospital have led an effort to identify, prevent and manage potentially harmful prescribing practices known as “prescribing cascades" (photo by Willie B. Thomas/Getty Images)

Kate Richards

Topic

Breaking Research

Temerty Faculty of Medicine

Dalla Lana School of Public Health

Leslie Dan Faculty of Pharmacy

Research & Innovation

Women's College Hospital

Medications are effective and powerful treatment options for protecting and advancing human health – but, if taken incorrectly, they can also cause harm, particularly among older adults who are taking multiple medications over long periods of time.

That’s why experts at the University of Toronto’s Leslie Dan Faculty of Pharmacy and Women’s College Hospital have led an effort to create a new tool for prescribers to identify, prevent and manage potentially inappropriate prescribing practices known as “prescribing cascades.”

Lisa McCarthy

“Prescribing cascades occur when a drug is prescribed to manage the side effects of another drug – often when a side effect is misinterpreted as a new medical condition,” says Lisa McCarthy, an expert in deprescribing and associate professor at the Leslie Dan Faculty of Pharmacy.

“Sometimes it makes sense to introduce a new drug to treat side-effects of another, but sometimes the prescriber doesn’t recognize that what they are seeing is, in fact, a drug-induced effect, and this can lead to inappropriate and potentially harmful prescribing.”

Inappropriate medication use as a result of prescribing cascades can put people at unnecessary risk of adverse drug events, reduced quality of life, as well as additional costs to individuals and health care systems.

To tackle the issue, McCarthy and her collaborators created a tool called ThinkCascades, which identifies nine clinically important prescribing cascades that affect older people when treating for common conditions such as anxiety, insomnia, hypertension or urinary incontinence.

The tool was recently presented in an article published in the journal Drugs & Aging.

"By identifying nine clinically important prescribing cascades, this tool helps clinicians recognize other prescribing cascades when managing polypharmacy,” says Paula Rochon, a senior scientist at Women’s College Research Institute, professor in the department of medicine in the Temerty Faculty of Medicine and Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health and founding director of the Women’s Age Lab based at Women’s College Hospital in Toronto.

“If we adjust our thinking to focus attention on raising awareness about prescribing cascades when reviewing medications, we can then work towards optimizing therapies and reducing medication harm for older adults, particularly women.”

While the research team notes there are many instances of prescribing cascades across health care globally, the nine included in the tool were selected by engaging a multidisciplinary panel of more than 30 clinicians from six countries with expertise in geriatric pharmacotherapy.

“Many clinicians struggle to identify prescribing cascades both conceptually and in clinical practice, which makes them underrecognized contributors to medication-related harm,” says McCarthy, who is also a clinician scientist at Trillium Health Partners. “In many ways, it’s really a problem that nobody sees. And when multiple prescribers are involved, responsibility for appropriate prescribing and patient education may also be unclear.”

But McCarthy notes there is growing awareness about the extent of preventable medication-related harm with the World Health Organization (WHO) identifying medication safety as the theme for its World Patient Safety Day, which was held Sept. 17. In addition to raising global awareness of the high burden of medication-related harm, WHO’s World Patient Safety Day aims to empower patients and families to be actively involved in the safe use of medications.

McCarthy says such involvement is an important aspect of reducing harm.

“We’ve seen that it’s not really on medical professionals’ radars to commonly think about drug-induced signs and symptoms, and so it becomes even more important for patients and families to understand their medications and to be prepared to ask, ‘Is what I’m experiencing related to my medication?’

“As health-care professionals, we need to be more aware and open to these discussions.”

More than vaccines: U of T researcher investigates the future of mRNA therapeutics

Christopher.Sorensen — Wed, 23 Feb 2022 16:52:31 +0000

More than vaccines: U of T researcher investigates the future of mRNA therapeutics

Christopher.Sorensen Wed, 02/23/2022 - 11:52

Cutline

An assistant professor at the Leslie Dan Faculty of Pharmacy, Bowen Li is an emerging expert in mRNA-based therapy, gene editing and immunotherapy (photo by Steve Southon)

Kate Richards

Topic

Our Community

Institutional Strategic Initiatives

Precision Medicine Initiative at U of T

Leslie Dan Faculty of Pharmacy

Research & Innovation

The arrival of COVID-19 thrust mRNA-based technologies into the spotlight two years ago – but Bowen Li’s interest in the technology was piqued pre-pandemic and extends well beyond vaccines.

An emerging expert in mRNA-based therapy, gene editing and immunotherapy, Li recently joined the University of Toronto’s Leslie Dan Faculty of Pharmacy where he works at the intersection of biomaterials sciences, drug delivery and immunoengineering.

He is launching a cutting-edge research program in his lab that’s dedicated to building nonviral delivery systems for nucleic acids including mRNA, siRNA and CRSIPR-Cas9. The rapidly evolving, highly interdisciplinary area of biomedicine is focused on tapping the potential of mRNA to encode therapeutic proteins to prevent or treat multiple diseases, including cancer.

“We’ve seen how mRNA therapeutics and delivery technology allowed for the rapid development of SARS-CoV-2 vaccines,” says Li, an assistant professor in the department of pharmaceutical sciences. “But it also promises to advance the development of treatments for a variety of other diseases including cancer, autoimmune diseases and genetic disorders by enabling patients to produce their own therapeutic proteins."

Prior to joining U of T, Li was a post-doctoral associate at the Massachusetts Institute of Technology (MIT) working with Professors Robert S. Langer and Daniel G. Anderson. Called the “The Edison of Medicine” by Harvard Business Review, Langer is a renowned expert in tissue engineering and regenerative medicine who, along with U of T alumnus Derrick Rossi, co-founded Moderna, Inc., the U.S.-based biotechnology company that developed one of the most prominent mRNA vaccines for COVID-19.

Li said that multi-disciplinary initiatives and collaboration opportunities were part of what drew him to U of T, as well as the connection to leading academic hospitals and clinical environments.

“Working with clinicians in the University Health Network and other academic hospitals will help us identify impactful and challenging clinical questions,” says Li. “I also look forward to collaborating with clinician scientists to test new mRNA therapeutics in their disease models to help expediate the translation of our technologies from the lab.”

Li’s research will also contribute to U of T’s PRiME precision medicine research initiative – in part because mRNA can be engineered to encode virtually any therapeutic protein of and can therefore be tailored to individual patient needs. “Using mRNA therapeutics confers tremendous flexibility and broader therapeutic utility than nearly all other classes of known drugs, providing the unprecedented opportunity to make personalized medicine a greater reality in the clinic,” Li says.

“We are very excited to have Dr. Li join our research faculty,” says Micheline Piquette-Miller, associate dean of research in the Leslie Dan Faculty of Pharmacy. “Therapeutics based on mRNA have become a leading technology in the area of vaccines and personalized medicine. There is great synergy of Dr. Li’s work with our current research initiatives, which serve to advance the discovery, development and use of novel therapeutics and diagnostics.

“Our faculty’s team of multi-disciplinary investigators welcome the opportunity to work together and collaborate on translating new discoveries to the clinic.”

Future promise of mRNA to treat disease

Li’s interest in mRNA technology began after he completed his PhD in Bioengineering at the University of Washington in 2019, where he learned about the considerable therapeutic potential of the approach. “The really exciting part is that it allows patients to produce their own therapeutic proteins rather than these proteins being produced in a lab setting,” says Li, explaining that developing proteins in the lab is more costly and time consuming. “When we can use the human body to create appropriate therapeutic proteins, we aren’t required to spend as much time on purification processes.”

However, while some advantages are clear, effectively delivering mRNA therapeutics to patients still faces bottlenecks because they can be unstable and vulnerable to breaking down before achieving their desired effects. “There is a need for more appropriate delivery systems such as lipid nanoparticles (LNPs) that can prevent enzymatic degradation of mRNA and help it reach the targeted human cells more effectively,” Li says.

Li is working to develop advanced delivery systems that improve the safety and effectiveness of mRNA therapeutics. In his past research, Li created a high-throughput combinatorial platform that can synthesize lipid-like materials and select the most effective one for mRNA delivery much quicker than what is currently available. Based on this groundbreaking platform, he has developed different types of mRNA lipid nanoparticles for a range of human health applications.

“We’ve led proof-of-concept demonstrations of immunostimulatory LNPs that increase the effectiveness of mRNA vaccines so that only one tenth of the doses currently being given in clinic would be needed to elicit protective immunity against SARS-CoV-2,” Li says. “If we can reduce the dosage required while still providing protective immunity, this will increase efficacy while reducing the side-effects people experience.”

At U of T, Li is moving the delivery technologies forward to further tap the potential of mRNA for creating new life-changing medicines. Most biomedical applications such as immunotherapy, gene editing and cell reprogramming require protein expression for only limited periods of time. This means that mRNA therapy holds significant promise because of its transient and non-integrating expression feature.

“Using mRNA to encode CRISPR-Cas9 will reduce the off-targeting risk because the injected mRNA will disappear in a few days. The nonviral delivery vectors we are investigating also tend to have better biosafety than other viral vectors,” Li says.

A dedicated teacher and mentor

Li is also an enthusiastic teacher and mentor. He has experience with students in his own lab, but also through volunteer work with the University of Washington’s Health Sciences Center Minority Students Program, and tutoring teenagers from Seattle’s Somali community. He helped find mentors of similar backgrounds pursuing science and research who could expose the teens to career possibilities.

This experience helped Li understand that a one-size-fits-all approach to learning or training is insufficient. “Not only do we have to be supportive, but we have to learn about a person’s background and experiences and help personalize their training plans,” he says.

Li is also the first in his family to go to university and found he had to look elsewhere for guidance and mentorship while pursuing his academic goals.

“When I needed guidance for my studies, I couldn’t get help from my family. Educators played a very important role for me, and now I want to take this responsibility on for others,” Li says. “I am well aware that being a faculty member does not mean just being successful in research. One should be excellent in their interactions with students and broader contributions to the community.”

Li strongly believes that diversity and inclusion lead to a broader pool of thought and are essential for success in academia.

“My goal is that my lab will provide a positive training experience for people with various different backgrounds and experiences and will produce a cadre of young scientists that can have a positive impact on human health.”

U of T's Discovery Pharmacy launches naloxone program for university community

Christopher.Sorensen — Thu, 03 Feb 2022 18:16:49 +0000

U of T's Discovery Pharmacy launches naloxone program for university community

Christopher.Sorensen Thu, 02/03/2022 - 13:16

Cutline

A fast-acting and potentially life-saving medication, naloxone can be used to counter the effects of an opioid overdose (photo by Steve Russell/Toronto Star/Getty Images)

Topic

Centre for Addiction and Mental Health

Lawrence S. Bloomberg Faculty of Nursing

Leslie Dan Faculty of Pharmacy

The Discovery Pharmacy at the University of Toronto’s Leslie Dan Faculty of Pharmacy is now piloting naloxone training for select offices and programs at the university.

A fast-acting and potentially life-saving medication, naloxone can be used to counter the effects of an opioid overdose the moment it is occurring. Much like an EpiPen is used to treat anaphylaxis, naloxone can be used by anyone with access to a kit and proper training.

“Providing naloxone kits and training is one way to help support the safety of our community and to help combat the effects of the ongoing opioid crisis,” said Jonathan Nhan, interim pharmacist lead at the Discovery Pharmacy.

In 2016, in response to the growing opioid crisis, naloxone kits became available without the need for a prescription nationally and free of charge in Ontario through the Ontario Naloxone Program and the Ontario Naloxone Program for Pharmacists. Since then, pharmacists have played a key role in dispensing take-home naloxone kits, a service that is coupled with one-on-one training and harm reduction counselling.

Maria Zhang, clinician educator at the Leslie Dan Faculty of Pharmacy and the Centre for Addiction and Mental Health (CAMH), has been working alongside Nhan to develop the Discovery Pharmacy naloxone program. The team of pharmacists and pharmacy students will be using resources originally developed by CAMH to deliver training at both the individual and group levels.

“We want to reduce the harms associated with drug use,” said Zhang, pointing out that many people can be exposed to opioids through different means. “Opioid poisoning can result from prescription opioid use as well as from taking recreational drugs that contain opioids – known or unknown – to the person taking them.”

Both Zhang and Nhan emphasize that maintaining individual privacy and reducing stigma associated with drug use are key to improving access to life-saving interventions. “Even if someone is interested in just learning more about the take-home kits, they can reach us at Discovery Pharmacy to ask questions,” said Nhan.

Stigma surrounding drug use can be a barrier to people accessing tools like naloxone – an issue the group training sessions aim to address.

The onset of the COVID-19 pandemic has exacerbated the opioid crisis. A September 2021 report from Ontario’s COVID-19 science advisory table outlined opioid overdose deaths increased by 60 per cent since the pandemic started in March 2020. Several subpopulations including men and individuals aged 20 to 49 are disproportionally impacted.

“We know that drug use can happen … and in isolation now more than ever. We want to contribute to the solutions addressing the opioid crisis with this service,” said Zhang.

In addition to the direct care delivery of providing naloxone kits and training, the Discovery Pharmacy program layers in the interprofessional education of health-care students, research and quality improvement.

“As an accredited pharmacy embedded in the U of T ecosystem, we aim to advance pharmacy practice and offer interprofessional care to our community,” said Zhang. “We also plan to interlay research and education and collaborate with other disciplines to see how we can better deliver our naloxone training, reach more people and destigmatize substance use so that those who require help don’t hesitate in getting it.”

Students and faculty from the Lawrence S. Bloomberg Faculty of Nursing will also play an active role in naloxone training and education through the Discovery Pharmacy. This provides a tangible opportunity for students to develop skills in interprofessional practice.

“For the most part, students across our health faculties learn within their respective fields. We talk about interprofessional practice in theory but often the first time a nursing student is exposed to it is when they are in hospital on clinical rotation,” said Sarah Ibrahim, assistant professor, teaching stream at the Lawrence S. Bloomberg Faculty of Nursing. “The more our students have the opportunity to gain interprofessional experience, the better equipped they will be once they are ready to enter practice.”

Nursing students will take initial training alongside pharmacy students and then will be paired up to provide peer-to-peer training. “This is a great way for students to come together to build that interprofessional partnership and rapport and carry this over as health-care providers,” said Ibrahim, who points out the need for health-care students to learn about harm reduction and the negative impact of stigma. “Stigma of drug use is a barrier for people accessing care and if, as a health-care provider, you don’t have the skills to provide care in this context, that’s also a barrier.”

Web-based version of U of T researcher's CARD game helps improve kids’ vaccination experience

Christopher.Sorensen — Thu, 16 Dec 2021 21:32:38 +0000

Web-based version of U of T researcher's CARD game helps improve kids’ vaccination experience

Christopher.Sorensen Thu, 12/16/2021 - 16:32

Cutline

The online version of the CARD game, originally developed by U of T's Anna Taddio, educates children, parents and caregivers on how to use evidence-based pain and anxiety management strategies during vaccination (photo by Steve Southon)

Topic

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Vaccines

With COVID-19 vaccines now available in Canada for kids five to 11 years old, many parents and caregivers are looking for ways to help younger children have a positive vaccination experience – and a system created by a University of Toronto researcher may be able to help.

Anna Taddio, a professor in the Leslie Dan Faculty of Pharmacy and a senior associate scientist at the Hospital for Sick Children in Toronto, and her team have developed a web-based version of the CARD game (short for Comfort, Ask, Relax and Distract) she originally created to help kids receiving vaccines in school-based programs. The system addresses fear of needles through pain management and coping strategies.

The new web-based version of the game is intended for younger kids who are currently being encouraged to get vaccinated.

“We want to help younger kids, especially now that they are eligible for COVID-19 vaccines,” Taddio said. “They can play the game on their own or with caregivers to learn how to cope with fear and pain during vaccination.”

Earlier this year, Taddio received federal funding to “design and implement pain mitigation strategies for adults” in support of the country’s mass vaccination campaign to combat the ongoing COVID-19 pandemic. As vaccines for COVID-19 first began to rollout in 2021, Taddio’s system was shared with health-care networks and the public to help people feel more comfortable when receiving their vaccinations. The CARD system has been used across the province including in specialized vaccination clinics run by the Centre for Addiction and Mental Health (CAMH) in Toronto, Wellington-Dufferin-Guelph Public Health and Ottawa Public Health.

In collaboration with Immunize Canada, the game was developed by Anthony Ilersich, a fourth-year student in the Faculty of Mathematics at the University of Waterloo.

“We developed the web-based game because if the material is interactive and easy to play online, it should be all the more effective,” said Ilersich who was the lead-developer on the CARD game project.

“Vaccination is our strongest defense against preventable diseases. It keeps our children, families, and communities healthy,” said Lucie Marisa Bucci, senior manager, Immunize Canada. “Immunize Canada is proud to have partnered on the CARDweb game because it applies the best evidence and all that we know to make the vaccination experience more positive for everyone.”

The CARD game addresses a fear of needles through pain management and coping strategies (photo courtesy of Immunize Canada)

The new game is web-based and accessible on any mobile device. Parents and kids can visit the Immunize Canada website to play the game and learn about coping strategies ahead of time. Children can then use the game as a coping strategy during the actual vaccination procedure.

“The new online CARDgame is not only an exceptional all-in-one resource for teaching kids how to reduce pain and anxiety during vaccination; it is also an important tool for every parent and caregiver preparing to vaccinate their child,” Bucci said.

Prior to the pandemic, Niagara Region implemented a paper-based CARD program across all schools in the area and, in 2015, Taddio’s HELPinKids&Adults Clinical Practice Guideline (CPG) about mitigating pain during vaccination was adopted across Canada and internationally, including by the World Health Organization.

Additional partners who collaborated on the CARD game include: Anxiety Canada, the Hospital for Sick Children, and the University of Guelph.

Lisa Dolovich to become new dean of U of T's Leslie Dan Faculty of Pharmacy

Christopher.Sorensen — Fri, 28 Feb 2020 17:45:15 +0000

Lisa Dolovich to become new dean of U of T's Leslie Dan Faculty of Pharmacy

Christopher.Sorensen Fri, 02/28/2020 - 12:45

Cutline

Lisa Dolovich, who is currently interim dean of the Leslie Dan Faculty of Pharmacy, says there's never been a greater need for pharmacists as choosing, using or stopping medications becomes increasingly complex (photo by Steve Southon)

Kate Richards

Topic

Our Community

Cheryl Regehr

Leslie Dan Faculty of Pharmacy

Professor Lisa Dolovich will become the University of Toronto’s next dean of the Leslie Dan Faculty of Pharmacy.

Dolovich, who is currently the faculty’s interim dean, will serve a five-year term beginning on July 1, 2020.

“I am proud to be part of an environment where our students, staff and faculty are recognized worldwide for remarkable scholarship, ingenuity, creativity and impact,” Dolovich said. “We are the top-ranked faculty of pharmacy in Canada and number four in the world, so it’s a great honour to take on the role of dean at U of T.”

A pharmacist and leading health services researcher, Dolovich is an internationally recognized scholar distinguished for her work on how individuals manage their medicine and health in the context of where they live. She has contributed to more than 200 peer-reviewed publications, has held more than $5 million in grants from the Canadian Institute of Health Research (CIHR) as a principal investigator, over $26 million from CIHR as a co-investigator and co-founded the Ontario Pharmacy Evidence Network.

“Professor Dolovich’s keen insights and collaborative style have helped to stabilize the faculty during a period of transition. Her concerted efforts to bring faculty, staff and students together to discuss, plan and implement changes have moved important priorities forward,” said Cheryl Regehr, U of T’s vice-president and provost.

In addition to being a leading professional pharmacy practice program, the Leslie Dan Faculty of Pharmacy is also home to the graduate department of pharmaceutical sciences and several prominent research centres where scientists and trainees investigate every aspect of the drug discovery process and the socioeconomic, ethical and safety implications of the use of medications. With more than 200 collaborations with leading scientists and institutions in over 40 countries across the world, the impact of the work is global.

“The research environment at our faculty is flourishing and I look forward to helping our faculty grow in our ability to make a lasting impact on health and society,” Dolovich said.

Like many other health professions, the practice of pharmacy is undergoing significant change. But with change comes opportunity, according to Dolovich.

“Our approach to choosing, using or stopping medications is becoming more complicated and so there has never been a greater need for pharmacist expertise within health-care systems.”