Precision Medicine Initiative at U of T

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 ��Ƶ’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.”

'The time for PRiME is now': Inaugural symposium looks at innovations in precision medicine

davidlee1 — Mon, 07 Oct 2019 04:00:00 +0000

'The time for PRiME is now': Inaugural symposium looks at innovations in precision medicine

davidlee1 Mon, 10/07/2019 - 00:00

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U of T's Christine Allen (left) and Shana Kelley at the PRiME symposium (all photos by Steve Southon)

Kate Richards

Topic

Our Community

Precision Medicine Initiative at U of T

Chemistry

Faculty of Arts & Science

Leslie Dan Faculty of Pharmacy

Research & Innovation

More than 200 ��Ƶ scientists and trainees, along with leaders from industry and community partners, attended the inaugural symposium for the Precision Medicine Initiative (PRiME) to share recent research innovations in precision medicine.

“The time for PRiME is now,” said Christine Allen, U of T's associate vice-president and vice-provost, strategic initiatives, as she kicked off the symposium.

Launched in April 2019, PRiME is a new cross-institutional effort that will establish Toronto as a leading centre for precision medicine. It brings together world-class scientists, engineers and clinicians from across four U of T faculties to tackle needs in drug discovery, diagnostics and disease biology.

“While the number of targeted therapies is increasing, the majority of patients still receive conventional therapies,” said Shana Kelley, University Professor at U of T’s Leslie Dan Faculty of Pharmacy and director of PRiME. “A multidisciplinary approach that goes beyond genomics and mutational profiling is required to accelerate new discoveries and realize the promise of precision medicine. We have that capability at U of T.”

PRiME postdoctoral researcher Margot Karlikow discusses her work investigating new diagnostic technology to detect infectious diseases rapidly and at a lower cost than conventional methods

The symposium featured research highlights from the first cohort of PRiME Fellows, 10 high-calibre U of T trainees who are undertaking projects that combine the expertise of at least two scientists from different faculties, forging many new cross-faculty collaborations.

Margot Karlikow is a postdoctoral researcher in Assistant Professor Keith Pardee’s lab in the department of pharmaceutical sciences at the Faculty of Pharmacy. Kalikow is also a PRiME Fellowship awardee working on a new diagnostic technology that blends synthetic biology and CRISPR to detect infectious diseases rapidly and at a lower cost than conventional methods. By connecting her with Professor Gilbert Walker’s team in the department of chemistry, her fellowship with PRiME will allow her to investigate how nanoparticles could be used to expand and potentially improve her diagnostic approach.

“PRiME is helping us bridge worlds to reach potential that we haven’t considered before, to see if you can push your innovation further,” she says. “This gives me the chance to explore an entirely new domain.”

PRiME will also function as a portal for industry to connect with U of T. Top leaders and innovation seekers from pharmaceutical and medical technology companies attended the symposium, with several participating in a panel led by Stéphane Angers, associate dean of research at the Faculty of Pharmacy and associate director of PRiME.

The panel discussed what factors contribute to successful academic-industry collaborations, the unique strength of Toronto in building new solutions that can be translated into clinical practice and affordability of new therapies.

“In Toronto you have an opportunity to get clinical and basic science closer together, to mix these two things efficiently,” said Michel Bouvier, CEO, Institute for Research in Immunology and Cancer (IRIC) referring to the close proximity of U of T’s affiliated hospitals as a great advantage. “This seems [like] something easy to do but it is quite difficult to achieve.”

Panelist Philip Tagari, vice-president of research at Amgen Inc., talked about the need to work upstream when it comes to managing disease. “We need to move away from the ‘break and fix’ mentality, to predict disease before it occurs so that [the patient] never has a hip fracture,” rather than waiting for hip fractures to occur and then treating them. “This is the challenge for the industry, but also the medical system as a whole,” he said.

“PRiME is off to a great start and we are building momentum every day,” said Kelley. “The partnerships we are developing will be critical to the success of our initiative and our ability to improve individual health outcomes and the sustainability of our health system overall.”

U of T researchers engineer antibodies that unlock body’s regenerative potential

noreen.rasbach — Tue, 27 Aug 2019 18:23:06 +0000

U of T researchers engineer antibodies that unlock body’s regenerative potential

noreen.rasbach Tue, 08/27/2019 - 14:23

Cutline

Stephane Angers (left) and Sachdev Sidhu: Their teams have engineered antibodies that can activate tissue repair and will be developed into regenerative medicine treatments (photo by Steven Southon)

Jovana Drinjakovic

Topic

Breaking Research

Precision Medicine Initiative at U of T

Donnelly Centre for Cellular & Biomolecular Research

Innovation & Entrepreneurship

Leslie Dan Faculty of Pharmacy

Medicine by Design

Molecular Genetics

Research & Innovation

Startups

Our body makes antibodies to fight infections. But the synthetic versions of these molecules could hold the key to stimulating the body’s ability to regenerate.

The findings come from a decade-long collaboration between the teams of Sachdev Sidhu, a professor in the Donnelly Centre for Cellular & Biomolecular Research, and Stephane Angers, associate dean of research in the Leslie Dan Faculty of Pharmacy, that have been creating synthetic antibodies for diverse applications.

Antibodies are increasingly being developed into drugs thanks to their ability to bind and affect the function of other proteins in cells. Because they are encoded by genes, antibodies can be created in the lab using genome and protein engineering technologies.

Now Sidhu and Angers’ teams have created antibodies that could one day stimulate tissue in the body to repair itself, as described in a study published online in eLIfe, an open-access journal. A newly launched Toronto startup, AntlerA Therapeutics, will turn the antibodies into drug-like molecules for regenerative medicine.

The work was done in collaboration with the Toronto Recombinant Antibody Centre, co-founded by Sidhu in the Donnelly Centre, which has created a massive catalogue of synthetic antibodies for research and drug discovery.

“We are developing new molecules that have never been seen before and whose potential for regenerative medicine is enormous,” says Sidhu, also a professor in U of T’s department of molecular genetics and co-founder of AntlerA.

“By capitalizing on the momentum of stem cells research and regenerative medicine that already exists in Toronto, we are ideally situated to commercialize these molecules.”

Both Sidhu and Angers are members of the recently launched Precision Medicine Initiative (PRiME) at U of T that seeks to accelerate treatments targeting the biological underpinnings of an individual’s disease. The team recently obtained support from the Medicine by Design program.

The antibodies were engineered to mimic key growth factors, proteins called Wnt (pronounced as “wynt”) that normally instruct stem cells – cells that can turn into any cell type in the body – to form tissue in the embryo. Wnt proteins also activate stem cells for tissue repair following injury in adults, while mistakes in Wnt signaling can lead to cancer.

Scientists have long sought to co-opt Wnt as a tool for activating tissue regeneration. But these efforts were stymied by the molecules’ complicated chemistry – Wnt proteins are attached to fat molecules, or lipids, which makes their isolation in active form difficult.

“People have been trying for decades to purify Wnt proteins and make drugs out of them,” says Sidhu. “Drug development would require further engineering of Wnt proteins. But Wnt are difficult to purify, let alone engineer – therefore they unlikely become drugs.”

The associated lipids also prevent Wnt proteins from dissolving in water, making them unsuitable as medicines because they cannot be injected.

That’s why the researchers decided to design antibodies that behave like Wnts, by binding to and activating two classes of Wnt receptors, Frizzled and LRP5/6, on the surface of cells, but are also water soluble and therefore easier to work with.

Called FLAgs, for Frizzled and LRP5/6 agonists, the antibodies can be designed to replicate any one of the hundreds possible Wnt-receptor combinations (humans have 19 different Wnt proteins that can activate 10 Frizzled and eight co-receptors including LRP5/6).

To generate FLAgs, Yuyong Tao, a postdoctoral researcher in Sidhu’s lab, came up with a new molecular configuration that does not exist in nature. Whereas natural antibodies have two binding sites, allowing them to bind to two targets, FLAgs have four, which means that a single molecule can recognize multiple receptors at the same time and mimic how Wnt proteins act in the body.

When added to cell culture, FLAgs were able to substitute for Wnt proteins – a hard-to-source but necessary ingredient in culture medium – and stimulate the formation of stem cell-derived intestinal organoids, three-dimensional balls of tissue that resemble the small intestine.

“These 3D organoids hold great potential for research and drug discovery but to grow them you need a source of Wnt proteins to activate stem cells,” says Angers, whose team presented the findings earlier this month at an eminent Gordon research conference in the U.S. “Now we have a defined protein, which we can easily obtain in large amounts and which can support the growth of organoids from various tissues.”

“This is going to be really important and transformative for a lot people in the field,” he says.

Most strikingly, when injected into mice, the FLAgs were able to activate the gut stem cells, showing that the antibodies are stable and functional inside the body. The finding raises hopes that FLAgs could be used as treatment for irritable bowel disease and other ailments to regenerate the intestinal lining when it is damaged. Other FLAg variants show promising results in lung, liver and bone regeneration as well as having the potential for treating eye disease.

AntlerA has already attracted investment to develop FLAgs into cutting edge therapeutics and is actively working on treatments for vision loss and bowel diseases. The startup’s name was inspired by FLAgs’ geometrical shape which resembles the antlers of deer and moose which are the fastest regenerating organs in animals.

“The type of discovery we report in our study was possible with a convergence of expertise,” says Angers, co-founder of AntlerA. “Thanks to the close collaboration and proximity between our labs, we were able to apply protein engineering to activate a critical stem cell signaling pathway with the ultimate goal to develop regenerative medicine promoting the repair of diverse tissues in the body.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, Genome Canada, the Ontario government and the Canada First Research Excellence Fund.