Medicine by Design

Donnelly Centre for Cellular & Biomolecular Research

Leslie Dan Faculty of Pharmacy

Parkinson's

Subheadline

An antibody was used to selectively activate a receptor in a molecular signalling pathway to develop dopaminergic neurons

Researchers at the �ؿ�ζSM believe they’ve found a way to better control the generation of key neurons depleted in Parkinson’s disease – suggesting a potentially new approach to addressing a disease with no cure and few effective treatments.

In preclinical studies, the researchers used an antibody to selectively activate a receptor in a molecular signalling pathway to develop dopaminergic neurons. These neurons produce dopamine, a neurotransmitter critical to brain health.

While researchers around the world have been working to coax stem cells to differentiate into dopaminergic neurons to replace those lost in patients living with Parkinson’s disease, the efforts have so far been hindered in part by an inability to target specific receptors and areas of the brain.

“We used synthetic antibodies that we had previously developed to target the Wnt signaling pathway,” said principal investigator Stephane Angers, who is director of U of T’s Donnelly Centre for Cellular and Molecular Biology and a professor in the Leslie Dan Faculty of Pharmacy and the Temerty Faculty of Medicine.

“We can selectively activate this pathway to direct stem cells in the midbrain to develop into neurons by targeting specific receptors in the pathway. This activation method has not been explored before.”

Parkinson’s disease is the second-most common neurological disorder after Alzheimer’s, affecting over 100,000 Canadians. It particularly impacts older men, progressively impairing movement and causing pain as well as sleep and mental health issues.

Most previous research efforts to activate the Wnt signaling pathway relied on a GSK3 enzyme inhibitor. This method involves multiple signaling pathways for stem cell proliferation and differentiation, which can have an unintended effect on the newly produced neurons and activate off-target cells.

“We developed an efficient method for stimulating stem cell differentiation to produce neural cells in the midbrain,” said Andy Yang, first author on the study and a PhD student at the Donnelly Centre. “Moreover, cells activated via the FZD5 receptor closely resemble dopaminergic neurons of natural origin.”

Another promising finding of the study, published recently in the journal Development, is that implanting the artificially-produced neurons in a rodent model with Parkinson’s disease led to improvement of the rodent’s locomotive impairment.

“Our next step would be to continue using rodent or other suitable models to compare the outcomes of activating the FZD5 receptor and inhibiting GSK3,” said Yang. “These experiments will confirm which method is more effective in improving symptoms of Parkinson’s disease ahead of clinical trials.”

The research was supported by U of T’s Medicine by Design program, an institutional strategic initiative that receives funding from the Canada First Research Excellence Fund and the Canadian Institutes of Health Research.

Medicine by Design, CCRM launch alliance to bolster Canada’s leading position in regenerative medicine

Christopher.Sorensen — Mon, 11 Dec 2023 16:35:12 +0000

Medicine by Design, CCRM launch alliance to bolster Canada’s leading position in regenerative medicine

Christopher.Sorensen Mon, 12/11/2023 - 11:35

Cutline

The alliance between Medicine by Design and CCRM aims to create end-to-end capacity from discovery to clinical translation and commercialization (photo by sommersby/Getty Images)

Topic

CCRM

Subheadline

The partnership will help build a strong pipeline of regenerative medicine technologies and therapies

The �ؿ�ζSM’s Medicine by Design initiative and CCRM, a non-profit that supports the development and commercialization of regenerative medicines, are launching a new strategic alliance that aims to unlock Toronto’s potential as a world-leading ecosystem for regenerative medicine.

The partnership, which was announced at Medicine by Design’s 8th Annual Symposium on Dec. 6, will see the organizations build on their existing strengths in bridging high-risk, high-reward research to industry expertise, biomanufacturing infrastructure and the clinic.

The goal of the alliance, whose key members also include the University Health Network (UHN) and U of T, is to create co-ordinated, end-to-end capacity that spans discovery through to clinical translation and commercialization.

“Medicine by Design has its deep academic network and track record of supporting world-class research across the Toronto Academic Health Science Network (TAHSN). CCRM has 12 years of success in launching and scaling cell and gene therapy companies at the interface of academia and industry,” said Allison Brown, executive director of Medicine by Design.

“With this alliance, CCRM is making an investment to sustain Medicine by Design’s discovery programs well into the future. It will enable us to build upon a strong regenerative medicine pipeline of breakthrough technologies and therapies that will ultimately provide health and economic benefits to Canada and the world.”

Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives, said the alliance is in keeping with U of T’s strategic plan, and will bring an array of benefits to academic-led innovation.

“In addition to the investment into Medicine by Design, for U of T, this partnership unlocks a global network of biomanufacturing expertise, infrastructure and a network of industry partners that expand beyond regenerative medicine – a strategic benefit to the research and clinical communities in Toronto,” said Cowen.

Launched in 2015 with the support of a $114-million investment from the Canada First Research Excellence Fund (CFREF), Medicine by Design has made large-scale, strategic investments in high-risk, high-reward research, advancing more than 190 projects. A U of T institutional strategic initiative, it has recruited world-class faculty and provided training programs to thousands of graduate students, post-doctoral fellows and other personnel at U of T and its affiliated hospitals.

CCRM, which is funded by the Government of Canada, Province of Ontario and academic and industry partners, has accelerated translation of scientific discovery into new companies and products, with a specific focus on cell and gene therapies.

Michael May, president and CEO of CCRM, said the collaboration will contribute to ensuring that the life-saving potential of regenerative medicine is realized and that a talent pool is developed that will position Canada as a leader in the global cell and gene therapy industry. “Medicine by Design and CCRM, put together, represent an end-to-end perspective of the bench-to-bedside process – research and discovery to company development to manufacturing to bringing the therapy to market,” said May.

He noted the alliance will leverage both U of T’s and UHN’s reputations for world-class research and medicine and tap into a network of regenerative medicine-focused faculty and clinicians, as well as experts from the social sciences and other non-STEM fields.

Brad Wouters, executive vice-president, science and research at UHN and a member of Medicine by Design’s executive committee, said the alliance will facilitate access to funding and infrastructure for the clinical translation of new cell and gene therapies being developed by Toronto investigators.

“Toronto is known globally for the strength of our stem cell and regenerative medicine accomplishments,” said Wouters, a senior scientist at the Princess Margaret Cancer Centre and professor in the department of medical biophysics in U of T’s Temerty Faculty of Medicine. “UHN is excited to build on our existing partnerships with CCRM through the Centre for Cell and Vector Production and Medicine by Design to support this strategic alliance and its goals to create end-to-end capacity in our ecosystem to create new medicines that will have global patient impact.

“From discovery through to clinical validation and manufacturing, we look forward to advancing the next generation of living therapies for our patients.”

Scientists create ‘cloaked’ donor cell, tissue grafts that escape immune system rejection

Christopher.Sorensen — Wed, 06 Dec 2023 16:16:29 +0000

Scientists create ‘cloaked’ donor cell, tissue grafts that escape immune system rejection

Christopher.Sorensen Wed, 12/06/2023 - 11:16

Cutline

Andras Nagy, a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI) and professor in U of T’s Temerty Faculty of Medicine, led research that created transplants in pre-clinical testing without the need for immune suppression

Jovana Drinjakovic

Topic

Sinai Health

Lunenfeld-Tanenbaum Research Institute

Subheadline

The findings could lead to advancements in cell therapies for type 1 diabetes and heart failure

Researchers at Sinai Health and the �ؿ�ζSM have developed a technology that may one day eliminate the need for immunosuppressive drugs in transplant patients.

Through genetic modification of donor cells, the researchers successfully created transplants that persisted long-term in pre-clinical testing without the need for immune suppression.

The findings raise hope that a similar strategy could be employed in human patients, potentially making transplantation safer and more widely available.

“Our work paves the way for an ‘off-the-shelf’ supply of cells for therapies that could be safely given to many patients,” said Andras Nagy, a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI) and professor in the department of obstetrics and gynaecology and the Institute of Medical Science at U of T’s Temerty Faculty of Medicine, who led the research.

The study was published in the journal Nature Biomedical Engineering.

Immune rejection poses a major challenge in donor cell therapy, said Nagy, who is Canada Research Chair in Stem Cells and Regeneration and has done seminal work in the field. In such cases, the recipient’s immune system recognizes the transplanted cells as foreign invaders and launches an attack, leading to rejection.

“Transplant and cell therapy patients are required to take immunosuppressive drugs – sometimes for the rest of their lives – to prevent their bodies from rejecting the transplant,” explained Nagy. The extended use of these drugs can lead to serious health issues, including recurring infections and an elevated cancer risk.

Scientists worldwide have been exploring various solutions, including creating therapeutic cells from the patient’s own cells or encapsulating donor cells in inorganic material for protection.

But these methods face challenges such as high costs, long preparation times and foreign body immune response, complicating their widespread and cost-effective application.

Stem cells have the unique ability to divide indefinitely and give rise to specialized cells that form our organs. They make an ideal source for cell therapies as large numbers of cells can be obtained and converted into desired cell types to replace those lost to disease or injury.

But there are major safety concerns: in addition to addressing immune-matching, scientists must ensure that no unwanted dividing cells remain in the transplant that could cause cancer in the future.

Nagy, who established Canada’s first human embryonic stem cell line in 2005, has dedicated his career to engineering safeguards for future cell therapies. In 2018, his team published a landmark paper in Nature about a drug-inducible “kill-switch” called FailSafe that protects from cancer by eliminating unwanted proliferating cells in transplants.

For the current study, postdoctoral researcher Jeff Harding and PhD student Kristina Vintersten-Nagy combined the kill-switch technology with a strategy they called “immune cloaking.”

Nagy’s team selected eight key genes that regulate how the immune system responds to threats, including foreign cells. Forced overexpression of these genes in mouse embryonic stem cells prevented the immune system from recognizing them as foreign.

The modification effectively created an immune cloak around the cells following their injection under the skin of genetically unmatched hosts.

“Patient safety is paramount, and Dr. Andras Nagy is globally renowned for his sustained efforts to develop safeguards for future cell therapies,” said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health, and a professor of molecular genetics at Temerty Medicine.

“This study demonstrates the combined potential of FailSafe and immune cloaking for the creation of a universal source of cells that could be applied to a multitude of diseases.”

Uncloaked cells are typically rejected within 10 days of transplantation. In contrast, the cloaked cells persisted for more than nine months at the endpoint of the experiment. “This is the first time that we’ve been able to achieve this length of time without rejection in a fully functional immune system,” said Nagy, who is also a professor at Monash University in Australia.

In another key finding, the researchers showed that unmodified cells can escape rejection when embedded into the tissue created by the cloaked donor cells below the skin surface. The protection extended to cells from another species, as shown by the ability of unmodified human cells to survive within a cloaked mouse graft.

This suggests that modified cells also act as an immune-privileged implantation site for unmodified cells, with implications for interspecies transplants. Researchers at other institutions are exploring the potential of pigs as donors because their organs are very similar in size and function to humans.

Building on this success, PhD student Huijuan Yang selected human counterparts of the eight immunomodulatory genes and used them to create the first FailSafe and cloaked human cells. Co-culturing these cells alongside human immune cells from an unmatched host revealed their ability to escape destruction, unlike their unmodified counterparts.

This shows that cloaking has the potential to work for human patients as well, said Nagy.

While the research is still at an early stage, it holds great promise for regenerative medicine and cell-based therapies. Nagy envisions injecting uncloaked insulin-producing cells, or islets, into subcutaneous cloaked tissue to treat diabetes. Subcutaneous cell delivery may be less risky for patients than the current approach, where islets are delivered into the liver and may interfere with its normal function, Nagy said.

“This study gives invaluable insights into elegant alternatives to the toxic consequences of conventional immunosuppression,” said Michael Sefton, scientific director of Medicine by Design, a U of T institutional strategic initiative focused on regenerative medicine that primarily funded the research, who is a University Professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering in U of T’s Faculty of Applied Science & Engineering.

“These findings significantly advance cell therapies that can help people who live with chronic diseases such as type 1 diabetes or heart failure.”

Beyond diabetes, Nagy is also developing applications for patients who have age-related macular degeneration, arthritis, chronic pain and lung diseases. To bring these advances to patients faster, he co-founded a startup company, panCELLa, which recently merged with the U.S. company Pluristyx to continue to develop safe and cost-effective clinical-grade, off-the-shelf cells for therapy.

The research was funded by Medicine by Design, U of T, the Canadian Institutes for Health Research, Canada Research Chairs program and Ontario Research Fund.

This story was originally published at Sinai Health.

Working across disciplines, U of T and UHN researchers are rapidly revolutionizing lung transplant surgery

Christopher.Sorensen — Tue, 29 Nov 2022 14:28:25 +0000

Working across disciplines, U of T and UHN researchers are rapidly revolutionizing lung transplant surgery

Christopher.Sorensen Tue, 11/29/2022 - 09:28

Cutline

(Photo by Phira Phonruewiangphing via Getty Images)

Tina Adamopoulos

Topic

Groundbreakers

Artificial Intelligence

Hundreds of people in North America die each year waiting for a lung transplant – but it has little to do with a lack of donors.

About 80 per cent of donated lungs are deemed unsuitable for transplant, according to the International Society for Heart and Lung Transplantation. That’s because lungs are much more vulnerable to damage and deterioration than other organs.

But Shaf Keshavjee is working on a way to restore donated lungs – and help save lives.

Shaf Keshavjee

He’s the architect of a system called Ex Vivo Lung Perfusion (EVLP) that preserves lungs outside the body in a transparent dome, so doctors can better prepare them for transplant. The system keeps donated lungs intact for up to 12 hours.

“We’ve taken everything we know about lung ventilation, how to look after an injured lung and the perfusion of [blood through] the lung together, to create a protective system outside of the body,” says Keshavjee, a surgeon-in-chief at the Sprott Department of Surgery at the University Health Network (UHN) and professor in the department of surgery at the �ؿ�ζSM.

“People have tried to do this for almost 100 years.”

Keshavjee is continuing his work to refine the EVLP system as the lead investigator of the Organs by Design project. His research work is funded by U of T’s Medicine by Design (MbD) – a strategic initiative that brings together researchers at U of T and its affiliated hospitals at the convergence of science, engineering and medicine, to advance regenerative medicine discoveries and improve health outcomes. MbD is supported by Canada First Research Excellence Fund (CFREF).

To find solutions, each initiative draws on the breadth and depth of research at U of T, one of the world’s top public research universities, by bringing together flexible, multidisciplinary teams of researchers, students and partners from industry and government.

Increasing the number of healthy lungs for donation is one such challenge – and it’s far from the only lung transplant-related innovation that’s being advanced by U of T’s strategic initiatives.

Keeping lungs alive, outside of the body

Stored in a glass dome that maintains temperature, humidity and sterilization, the EVLP system gently maintains the lung with a ventilator and filter system that ensures an adequate supply of oxygen, blood, nutrients and protein to the organ.

Prior to transplantation, the lung is reassessed for tissue elasticity, blood vessel pressure and oxygen capacity.

Keshavjee built the EVLP technology alongside Marcelo Cypel, a thoracic surgeon at UHN and professor of surgery at U of T. The researchers are building on a legacy of ground-breaking research in lung transplantation in Toronto that stretches back decades. That includes a team of surgeons at Toronto General Hospital (TGH), led by the hospital and U of T’s Joel Cooper, who performed the first successful human lung transplant operation in 1983.

In addition to restoring damaged lungs, the EVLP system provides surgeons with more information that can improve their ability to achieve a successful transplantation.

Keshavjee’s team is also working on a diagnostic tool that will allow surgeons to make rapid decisions based on crucial data collected by the EVLP system.

Retrieving life-saving data in minutes

Andrew Sage, an assistant scientist at UHN’s Toronto General Hospital Research Institute and sessional lecturer at U of T, is building rapid diagnostics to swiftly supply doctors with a roadmap for lung repair.

Andrew Sage

The map is needed because lung transplant operations are a race against time – and doctors need to make rapid decisions based on the best available information.

“When we put lungs on the EVLP platform, we are able to generate a tremendous amount of information on the ability of the lung to properly function and, importantly, this data represents lung function in isolation – free from confounding signals that arise from the rest of the body,” Sage says.

“Our goal is to develop novel testing modalities that can provide detailed information to the surgeon to make enhanced decisions about the organ.”

The rapid diagnostics tool – called the Toronto Lung Score – quickly details the injury status of the organ, inflammation and likelihood of ideal post-transplant outcomes, among other information, based on a small sample of solution that travels through the lungs on the EVLP system. It’s being developed in partnership with SQI Diagnostics, a Toronto-based diagnostics development company.

At present, the tool provides results in under 40 minutes, but the team is working to trim the response time to less than 15.

The next step? Bo Wang, a professor at the Temerty Centre for Artificial Intelligence Research and Education in Medicine, is working with the team to explore how AI and computer science can further improve analysis so practitioners can learn more from the ex vivo circuits.

A new gold standard to store transplant lungs

Ana Cristina Andreazza is working on better ways to keep donor lungs healthy in the EVLP system – all of which promises to translate into better outcomes for patients.

Ana Cristina Andreazza

Andreazza, a professor in the departments of psychiatry and pharmacology and toxicology in the Temerty Faculty of Medicine, is leading efforts to improve storage of donated lungs through her research work with the Mitochondrial Innovation Initiative (MITO2i).

Andreazza heads an interdisciplinary team as scientific director of MITO2i. Made up of a network of clinicians, advocates and researchers across the university, NGOs and strategic partners, MITO2i is an ISI that discovers and supports new technologies and integrative platforms to understand the role mitochondria play in a wide range of diseases and how treating mitochondrial dysfunction can be therapeutic – and transform how clinicians approach the diagnosis and treatment of disease.

While the gold standard to store a transplanted lung is currently 4 C, Andreazza says the temperature puts the organ’s mitochondria – the powerhouses of cells – into a dormant state that could be impairing transplant outcomes.

“If we think through the lens of mitochondria metabolism, 4 C is not ideal,” says Andreazza, whose team is providing a better understanding of mitochondria’s role in human health and disease.

“When you transplant them from 4 C to a 37 C human body, you can imagine the clash that would happen.”

Working with Cypel, the surgeon at UHN, they found that increasing the temperature to 10 C better preserves mitochondria during EVLP, reducing the risk of rejection following transplant surgery.

A proof-of-concept pilot study, published last year in Science Translational Medicine, found that recipients of transplant lungs stored at 10 C required a ventilator for less than two days following surgery, on average. They demonstrated no signs of one of the earliest complications of a lung transplant, such as shortness of breath or dry cough, three days after the procedure.

A warmer storage temperature also prolongs the time donor lungs can be safely preserved, from the current maximum of six-to-eight hours, to between 10 and 16 hours. This, in turn, makes international organ transport possible, increasing availability for patients on waitlists.

Looking ahead, researchers at MITO2i are seeking answers to three key questions. Are there better ways to monitor mitochondria? Can unhealthy organs be repaired? And how can mitochondria be improved before organ transplantation?

Mapping the genetic variation of mitochondria

Enter Erika Beroncal, project manager at MITO2i and a master’s student in the department of pharmacology and toxicology in the Temerty Faculty of Medicine.

Erika Beroncal

One of 13 recipients of MITO2i’s 2022 Graduate Student Scholarship Awards, Beroncal is embarking on a research project to examine the genetic variance of mitochondria and its importance in lung transplant success.

She recently presented the project at the second annual MITO2i Research Symposium, a two-day virtual event that brought faculty, students and research partners together to share new developments in mitochondrial research and medicine.

Ultimately, Beroncal hopes to contribute to knowledge that will open doors for novel therapeutic interventions to enhance lung transplant outcomes.

“By working with people across disciplines to produce knowledge about mitochondria, I’m seeing current developments and learning how it affects real life,” Beroncal says.

“Through my research work, I know I’m able to make an impact in this field.”

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.

Students push the boundaries of research and innovation: Groundbreakers S2 Ep.4

Christopher.Sorensen — Tue, 08 Nov 2022 15:04:32 +0000

Students push the boundaries of research and innovation: Groundbreakers S2 Ep.4 Christopher.Sorensen Tue, 11/08/2022 - 10:04

Topic

Groundbreakers

Alumni

Robotics

U of T Mississauga

From launching rovers into space to exploring whether green cannabinoids can treat epilepsy in children, students at the �ؿ�ζSM are taking research and innovation in bold new directions.

In Ep. 4 of the Groundbreakers video series, host Ainka Jess goes behind the scenes with student researchers from the Robotics Institute and Medicine by Design strategic initiatives, as well as the Black Founders Network.

Some of their work is literally out of this world.

“I think as humans we are very curious creatures and I see planetary robots as a way to extend our reach in the solar system, so I’m actually really excited about what these rovers can do in the future,” says Olivier Lamarre, a PhD candidate in planetary robotics at U of T’s STARS Laboratory.

The episode also features Kareem Abdur-Rashid and Kamaluddin Abdur-Rashid – both alumni of U of T and co-founders and co-directors of Kare Chemical Technologies – and Justine Bajohr, a PhD candidate in the lab of Maryam Faiz, an assistant professor in the department of surgery in the Temerty Faculty of Medicine.

Groundbreakers is a multimedia series that includes articles at U of T News and features research leaders involved with U of T’s Institutional Strategic Initiatives, whose work will transform lives.

Watch S2 Ep.4 of Groundbreakers

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

Groundbreakers

PRiME

Donnelly Centre for Cellular & Biomolecular Research

Chemistry

Faculty of Arts & Science

Leslie Dan Faculty of Pharmacy

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.”

Experts explore strategies for strengthening Canada’s bioinnovation ecosystem at Medicine by Design event

Christopher.Sorensen — Wed, 05 Jan 2022 17:06:42 +0000

Experts explore strategies for strengthening Canada’s bioinnovation ecosystem at Medicine by Design event

Christopher.Sorensen Wed, 01/05/2022 - 12:06

Cutline

Toronto’s MaRS Discovery District, which shares close connections to U of T and its hospital partners, is a major Canadian hub for biotechnology innovation in Canada (photo by Makeda Marc-Ali)

Topic

Donnelly Centre for Cellular & Biomolecular Research

Institute of Health Policy Management and Evaluation

Munk School of Global Affairs & Public Policy

CCRM

Dalla Lana School of Public Health

Faculty of Applied Science & Engineering

Faculty of Arts & Science

What can the unprecedented speed of vaccine development during the COVID-19 pandemic teach us about strengthening our bioinnovation ecosystem?

For David Walt, a professor at the Wyss Institute for Biologically Inspired Engineering at Harvard University, many of the pandemic’s innovations promise to have a lasting effect since, as a society, we “now have some of the tools in place to help catalyze continued innovation and collaboration” in the field.

“Everyone who was working on [COVID-19] had the potential to be affected by it. It was a global imperative that we all co-operate,” he said during a recent symposium hosted by the �ؿ�ζSM’s Medicine by Design program.

Walt, who co-leads the Mass General Brigham Center for COVID Innovation, made the remarks during a panel discussion titled “Strengthening Our Bioinnovation Ecosystem” that followed his plenary talk.

David R. Walt

The symposium – “A Systems Approach to Regenerative Medicine” – was held over two days and attracted more than 500 registrants. It included talks from invited speakers Ruslan Medzhitov, a professor in the Yale School of Medicine at Yale University, on the topic of inflammation systems biology; and Linda G. Griffith, a professor in the department of biological and medicalengineering at the Massachusetts Institute of Technology (MIT), who spoke about organ-on-chip technologies, including their application to endometriosis.

The panel discussion on strengthening the bioinnovation ecosystem looked at the symposium’s broad theme in a more “holistic fashion,” said Medicine by Design Executive Director Michael Sefton, who is also a University Professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering.

“[We’re] looking at health-care systems and innovation systems with a focus on health policy and social science lessons learned from COVID-19.”

The panel discussion was timely as Medicine by Design seeks to ensure the bioinnovation system in Canada is well-prepared to advance the regenerative discoveries coming out of the labs of researchers at U of T and its partner hospitals.

“We are looking forward to continuing to excel and to prepare the future of human health – to continue to transform but also translate,” said Sefton, whose lab is located at the Donnelly Centre for Cellular & Bimolecular Research, in his opening remarks. “Our goal is to not just write great papers but to also show that these papers can be translated into impact –maybe not immediately, but certainly over the next five or ten years, if not beyond.”

The impact of COVID-19 on the bioinnovation pipeline was just one of themes panelists touched on during a wide-ranging discussion. The panel was moderated by Shiri Breznitz, who is an associate professor at the Munk School of Global Affairs & Public Policy and the director of the master of global affairs program at U of T.

A clinical pull rather than technology push

Often innovations begin with an engineer or scientist inventing a technology and filing a patent before determining the clinical need for their product. But using “design thinking” to innovate can accelerate the timeline of implementation by years, Walt said during his talk.

“If you start with the clinical need first rather than the technology – a clinical pull rather than a technology push – then you come up with a [design-thinking] model.”

In the design-thinking model, clinicians identify unmet needs and then scientists and engineers develop solutions to solve those problems. Design thinking “starts with the problem. It has a human-centred core,” said Walt.

Collaboration and trust are important elements of an ecosystem

Catherine Beaudry

The strength of an ecosystem can be measured by its level of collaboration and trust, said panelist Catherine Beaudry, who leads the Partnership for the Organization of Innovation and New Technologies (4POINTO) and is a professor at Polytechnique Montréal.

“At the heart of all these models, you have to remember that it’s individuals who are collaborating with other individuals. The glue that maintains the ecosystem is trust.”

Beaudry pointed to the importance of having strong intellectual property policies and making sure innovators are collaborating with regulators early in the therapeutics or technology development process as important elements of building trust. She added that using more thoughtful metrics – key performance indicators, or KPIs – is also a key part of measuring the health of an ecosystem.

“Bean counting is not the way to go. We need to measure how organizations collaborate, whether these relationships last over time, and what comes out of them.”

Aligning towards a common goal

Beate Sander

Beate Sander, a scientist and the director of population health economics research for the Toronto Health Economics and Technology Assessment Collaborative (THETA), pointed to how the speed of vaccine development during the pandemic showed us how the seemingly impossible could be possible.

“The pandemic has shown that we cannot separate health and the economy,” said Sander, who is also an associate professor at the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health.

“[In the pandemic] everyone is rallying around similar goals. So everything aligned in a time of very high pressure, very high uncertainty. How do we move what we have now to post-pandemic times when all that pressure is gone, and everyone will be inclined to go back to what we’ve done previously?”

Sander is an expert in health technology assessment, a multi-disciplinary process that looks at the value of a technology from a wide range of perspectives – not just technical properties, but also many other factors including economic considerations, social and legal impacts and patient perspectives.

Where normally innovations would move through a linear process of approvals, Sander said things were very different during the pandemic, when many of the phases moved in tandem with each other instead of sequentially. Introducing health technology assessment earlier into the process of innovation would also help speed up the adoption of new technologies, Sander said.

At the pre-clinical stage, Sander said, provinces and territories were already planning vaccine rollouts. Health Canada accepted vaccine data on a rolling basis and data was shared with relevant parties much earlier than it normally would be.

“I hope that some of those characteristics will be maintained – [for instance] parallel review and not having to wait until each step is finished.”

Beaudry said COVID-19 demonstrated the importance of the government playing an active role in the innovation ecosystem.

“We need to de-silo the economy because innovation very often is a combination of knowledge from multiple disciplines and multiple sectors. With COVID the government has been forced to do that really quickly. We need to draw the lessons in terms of cross-sector cross agency collaboration.”

Support for new companies and access to risk capital play a large role

Michael May

For smaller companies to thrive in the bioinnovation ecosystem, collaboration is an important element, said Michael May, president and chief executive officer at CCRM (formerly the Centre for Commercialization of Regenerative Medicine).

“It’s about alignment of interests. Bringing groups together and understanding the common goal and focusing on that common goal. And it’s a recognition that multiple partners are required for success,” said May. “It’s amazing how much translation and commercialization get stopped by innovators feeling like they have to do it all on their own.”

Aside from collaborations, May said, financial resources play a large role. May contrasted the Canadian ecosystem with the ecosystem in Boston, which is well known for its biotechnology sector and has more access to capital.

“We get bogged down without the financial resources to bring people together … and we’re trying to fill gaps without those resources. [The CCRM model] was built on the premise that we needed to leverage small successes and infrastructure and investments over time to enable access to capital.”

Walt, who has founded or co-founded several life sciences start-ups including multi-billion dollar biotech ventures Illumina, Inc. and Quanterix Corp., agreed that support for small companies is crucial.

“The small companies are at the core of innovation,” he said. “That’s where invention happens; that’s where all the creativity starts.”

Walt added that Boston and Canadian hubs like Toronto have many similarities. The biotech ecosystem in Boston started because there was a recognition that there was invention and innovation at the universities.

“[In Canada], there are great hubs where there’s concentrations of universities. That’s where most of these ecosystems start. They start with the intellectual capital, then they attract the venture capital, and then they attract more, and it just becomes a self-fulfilling enterprise.”

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen — Fri, 17 Dec 2021 20:40:18 +0000

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen Fri, 12/17/2021 - 15:40

Cutline

Juan Carlos Zúñiga-Pflücker and Sarah Crome are among the researchers working on generating pancreatic cells that can be transplanted to diabetes patients without being destroyed by their immune systems (photos courtesy of Medicine by Design)

Topic

Institute of Biomedical Engineering

Insulin 100

Princess Margaret Cancer Centre

Sunnybrook Health Sciences

Toronto General Hospital

Resarch & Innovation

Stem Cell

In a person with type 1 diabetes, the body mistakenly attacks pancreatic cells that produce insulin, a hormone responsible for regulating blood sugar.

Without insulin, serious and eventually fatal symptoms will occur. Yet, imagine if, instead of needing daily insulin injections, people with diabetes could have insulin-producing cells placed back into the body, fixing the problem at its source. This is the vision of a Medicine by Design-funded research team.

The approach is not without its challenges.

“Scientists are able to generate pancreatic cells from stem cells in the lab, and they can be transplanted to someone who has lost pancreatic function, but they’ll be reattacked by the immune system,” says Juan-Carlos Zúñiga-Pflücker, senior scientist at Sunnybrook Research Institute and professor of immunology in the Temerty Faculty of Medicine. “What our work is meant to do is enable those transplants to be broadly acceptable so anyone can benefit from transplanted therapies. But the barrier of the immune system is a difficult thing to overcome, and even more so in the context of autoimmunity.”

The cells are attacked because the immune system recognizes them as harmful invaders instead of helpful therapies. It is a complex problem that demands a complex strategy – and that strategy is an emerging area of research called immunoengineering, which uses bioengineering techniques to manipulate the immune system.

The only way to currently suppress the immune system is through drug treatments, but they’re not selective; they suppress the whole immune system and leave people vulnerable to infection and illness.

The team’s strategy aims to be more precise. They want to finely tune the immune system to maintain a healthy system while not rejecting a therapeutic transplant.

Zúñiga-Pflücker says a collaborative effort is important in solving this major challenge to regenerative medicine. “We can optimize cell types and engineer effective tissues in our separate labs. But if we don’t come together to create better tools to engineer the immune system, these therapies will not be usable. It’s something very fundamental.”

The team is one of 12 sharing nearly $21 million in funding from Medicine by Design over three years. Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Though the research could be applied broadly across regenerative medicine therapies, type 1 diabetes makes an ideal test case, says Zúñiga-Pflücker, who is also chair of the department of immunology.

“Not only is diabetes an autoimmune disease, where the diabetic’s own immune system attacks and kills insulin producing cells, but attempts to replace the lost cells with transplanted cells are also challenged by other impacts of the disease, as well as the presence of auto-reactive immune cells,” he says. “This makes it a powerful test case for our research since we can test the transplants under multiple immune stresses.”

Zúñiga-Pflücker leads the project, which brings the work of six different labs together.

Two labs, led by the Temerty Faculty of Medicine’s Maria Cristina Nostro, a senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute; and Sara Nunes Vasconcelos, a scientist at UHN’s Toronto General Hospital Research Institute, are using stem cells to generate tissues containing insulin-secreting cells for transplants.

Zúñiga-Pflücker says that this arm of the project is well ahead of schedule. “The Nostro and Vasconcelos labs are defining the right conditions that are necessary for generating insulin-producing cells, which are called islet cells. They’re creating newer and more effective ways to make these tissues.”

Nostro and Vasconcelos are also associate professors at U of T in the department of physiology and Institute of Biomedical Engineering, respectively.

The tissues created in their labs will be used to test the work of the other four labs involved in the project, which are concerned with engineering the immune reaction. And here, each of these labs is bringing a piece of the puzzle.

Read about research into therapeutic cell “cloaking”

Zúñiga-Pflücker and Naoto Hirano, a senior scientist at Princess Margaret Cancer Centre and a professor of immunology at U of T, work on producing regulatory T cells (Tregs). These cells can supress immune response and play a role in preventing autoimmune diseases like diabetes.

In earlier Medicine by Design-funded research, Zúñiga-Pflücker and Hirano came up with a method for producing T cells in a defined way. Some of the key breakthroughs developed as part of this research helped lay the foundation for Notch Therapeutics, a company co-founded by Zúñiga-Pflücker, which closed an $85-million (U.S.) Series A financing earlier this year.

Now, in the current research project, the two labs are crafting methods for producing Tregs and investigating how harnessing the power of other types of immune cells to work alongside the Tregs can induce the immune system to tolerate transplanted therapies.

The third investigator is Tracy McGaha, whose lab is looking at the role of macrophages, a type of white blood cell that that typically helps to attack foreign substances but can also play a role in repairing damaged tissues. McGaha is a senior scientist at Princess Margaret Cancer Centre, UHN, and a professor in the department of immunology in the Temerty Faculty of Medicine.

A fourth lab, led by Sarah Crome, is investigating a family of immune cells called innate lymphoid cells (ILCs), which act within tissues to help induce and modulate immune responses.

“We know several immune cell populations we individually study can protect from harmful immune responses and promote immune tolerance,” says Crome, who is a scientist at the Toronto General Hospital Research Institute, UHN, and an assistant professor of immunology at U of T. “The trouble is when you get into a situation that combines an autoimmune disease with rejection that can occur following islet transplantation, it’s a real challenge shutting down multiple harmful and sustained immune responses.”

Crome says that there are many different types of ILCs, so her work focuses on narrowing down which types of ILCs are best to use along with the Tregs.

Right now, each of the four labs working with immune cells are optimizing their cell types and techniques, and then, Crome says they will bring all their “best players” together.

“We’re really looking at harnessing whole networks of cells, instead of just looking at one cell population at a time. It’s bringing all of our collective expertise together into one project that makes this a powerful approach.”

Zúñiga-Pflücker says Medicine by Design has been instrumental in uniting this team of experts.

“Thanks to Medicine by Design’s support of our immunoenigneering program, we’re able to bring together multiple research sites within the �ؿ�ζSM and affiliated research institutes; UHN’s Princess Margaret Cancer Centre, Toronto General Hospital Research Institute and McEwen Stem Cell Institute; and Sunnybrook Research Institute.”

Medicine by Design-funded researchers generate cells to treat bile duct disorders resulting from cystic fibrosis

Christopher.Sorensen — Mon, 22 Nov 2021 17:23:18 +0000

Medicine by Design-funded researchers generate cells to treat bile duct disorders resulting from cystic fibrosis

Christopher.Sorensen Mon, 11/22/2021 - 12:23

Cutline

An image of the bile duct cells, or cholangiocytes, derived from stem cells (Image courtesy of Mina Ogawa)

Topic

Hospital for Sick Children

Stem Cells

Researchers at the �ؿ�ζSM and its partner hospitals have discovered a way to generate functional cells from stem cells that could open new treatment avenues for people with cystic fibrosis who have liver disease.

Funded by Medicine by Design and completed with the collaborative efforts of multiple labs, the research was recently published in Nature Communications.

While cystic fibrosis is well known as a lung disease, the second most common cause of death in patients is actually liver disease. This is because people with cystic fibrosis can experience a decrease in the flow of bile fluid, which is secreted by the liver that helps with digestion and detoxification. The bile duct is a tube-like structure found in the liver that carries bile to the small intestine. The loss of flow leads to liver dysfunction. As a result, some patients require liver transplantation.

Shinichiro Ogawa

“Until now, we have not had a good scientific model to study the human liver’s bile duct system physiologically,” says senior study author Shinichiro Ogawa, an affiliate scientist at the McEwen Stem Cell Institute and Ajmera Transplant Centre, University Health Network (UHN), and an assistant professor in U of T’s department of laboratory medicine and pathobiology.

“In order to study a disease in a dish at the basic cellular and molecular level, we need functional cells. The fact that we can derive these functional cells from stem cells gives us a totally different way of evaluating and treating defective cells.”

The cells that the researchers generated have the properties of mature, functional cholangiocyte cells, which are the cells that make up the bile duct. Cholangiocytes play a role in several chronic and progressive liver diseases that have few medical treatment options. These diseases are responsible for about 20 per cent of adult liver transplants and most pediatric liver transplants.

Not much is known about the bile duct disorders that can lead to liver disease, but Ogawa says this research may lead to a deeper understanding of the specific mechanisms of the disease, as well as being a powerful tool for finding new treatments.

Ultimately, the researchers say it may be possible to develop therapies that involve transplanting the cells into a patient who has bile duct disease, bypassing the need for a transplant.

The work is funded through Medicine by Design’s large team projects. Ogawa and his co-investigator Christine Bear, a senior scientist in molecular medicine at The Hospital for Sick Children and a U of T professor of physiology, are part of a team focused on harnessing the liver’s power to regenerate.

Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative at U of T and its affiliated hospitals that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Ogawa says it was the work of many different researchers and labs that brought the study together.

Beginning with pluripotent stem cells, which have the capacity to give rise to most of the cell types in the human body, Mina Ogawa, scientific associate at the McEwen Stem Cell Institute, was able to identify methods to efficiently guide the stem cells through the process of changing into cholangiocytes. Donghe Yang – a PhD candidate in the lab of Gordon Keller, who is director of UHN’s McEwen Stem Cell Institute – analyzed the stem cell-derived cholangiocytes at a single cell level to compare to human cholangiocytes in the liver.

The team used earlier Medicine by Design-funded research on the Human Liver Map to confirm that the cells they developed had the characteristics of mature cells, which are more functional and have more therapeutic applications as opposed to immature cells.

Researchers in Bear’s lab – Janet (Jia-Xin) Jiang, research project co-ordinator, and Sunny Xia, PhD student – were able to demonstrate that the cells were functional and responded to natural environmental cues like the force associated with fluid transport. Their work also showed that newly developed stem cell-derived cholangiocytes could, in the future, play a powerful role in developing organ-specific therapies.

“These studies highlight the importance of generating mature cells from stem cells that faithfully mimic the functional properties of the native tissue,” says Bear. “We can better understand the real effect of disease-causing mutations and cystic fibrosis therapies, especially in those hard-to-access organs”.

Bear adds that this work was made possible through an interdisciplinary effort. “This work is an excellent example of how collaboration among the research teams funded by Medicine by Design can help to target cutting-edge basic research in a way that will make a difference for patients.”

Ogawa says the power of stem cell technology is to be able to identify and correct the disease at a cellular level. One day, this research could lead to the development of personalized, customized treatments for other bile duct disorders. Ogawa adds that the McEwen Stem Cell Institute is a world leader in producing different cell types from these stem cells.

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj — Fri, 08 Oct 2021 10:57:51 +0000

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj Fri, 10/08/2021 - 06:57

Cutline

Andras Nagy (Photo provided by Sinai Health Foundation)

Paul Fraumeni

Topic

Institute of Biomedical Engineering

Insulin 100

Toronto General Hospital

Diabetes

Mount Sinai Hospital

Stem Cells