Gene Therapy

U of T researchers' AI model designs proteins to deliver gene therapy

Christopher.Sorensen — Mon, 29 Jan 2024 18:44:19 +0000

U of T researchers' AI model designs proteins to deliver gene therapy

Christopher.Sorensen Mon, 01/29/2024 - 13:44

Cutline

Michael Garton, left, an associate professor of biomedical engineering, and PhD candidate Suyue Lyu, right, used AI to custom-design variants of hexons that are distinct from natural sequences to help evade the immune system (photo by Qin Dai)

Qin Dai

Topic

Breaking Research

Institute of Biomedical Engineering

Artificial Intelligence

Faculty of Applied Science & Engineering

Gene Therapy

Graduate Students

Research & Innovation

Subheadline

Dubbed ProteinVAE, the model can be trained to learn the characteristics of a long protein using limited data

Researchers at the University of Toronto used an artificial intelligence framework to redesign a crucial protein involved in the delivery of gene therapy.

The study, published in Nature Machine Intelligence, describes new work optimizing proteins to mitigate immune responses, thereby improving the efficacy of gene therapy and reducing side effects.

“Gene therapy holds immense promise, but the body’s pre-existing immune response to viral vectors greatly hampers its success. Our research zeroes in on hexons, a fundamental protein in adenovirus vectors, which – but for the immune problem – hold huge potential for gene therapy,” says Michael Garton, an assistant professor at the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering.

“Immune responses triggered by serotype-specific antibodies pose a significant obstacle in getting these vehicles to the right target; this can result in reduced efficacy and severe adverse effects.”

To address the issue, Garton’s lab used AI to custom-design variants of hexons that are distinct from natural sequences.

“We want to design something that is distant from all human variants and is, by extension, unrecognizable by the immune system,” says PhD candidate Suyue Lyu, who is lead author of the study.

Traditional methods of designing new protein often involve extensive trial and error as well as mounting costs. By using an AI-based approach for protein design, researchers can achieve a higher degree of variation, reduce costs and quickly generate simulation scenarios before homing in on a specific subset of targets for experimental testing.

While numerous protein-designing frameworks exist, it can be challenging for researchers to properly design new variants because of the lack of natural sequences available and hexons’ relatively large size – consisting, on average, of 983 amino acids.

With this in mind, Lyu and Garton developed a different AI framework. Dubbed ProteinVAE, the model can be trained to learn the characteristics of a long protein using limited data. Despite its compact design, ProteinVAE exhibits a generative capability comparable to larger available models.

“Our model takes advantage of pre-trained protein language models for efficient learning on small datasets. We also incorporated many tailored engineering approaches to make the model suitable for generating long proteins,” says Lyu, adding that ProteinVAE was intentionally designed to be lightweight. “Unlike other, considerably larger models that demand high computational resources to design a long protein, ProteinVAE supports fast training and inference on any standard GPUs. This feature could make the model more friendly for other academic labs.

“Our AI model, validated through molecular simulation, demonstrates the ability to change a significant percentage of the protein’s surface, potentially evading immune responses.”

The next step is experimental testing in a wet lab, Lyu adds.

Garton believes the AI-model can be utilized beyond gene therapy protein design and could likely be expanded to support protein design in other disease cases as well.

“This work indicates that we are potentially able to design new subspecies and even species of biological entities using generative AI,” he says, “and these entities have therapeutic value that can be used in novel medical treatments.”

The research was supported by the Canadian Institute of Health Research and the Natural Sciences and Engineering Research Council of Canada.

Medicine by Design to accelerate regenerative medicine discovery and translation with new $20-million investment

davidlee1 — Fri, 11 Oct 2019 15:52:34 +0000

Medicine by Design to accelerate regenerative medicine discovery and translation with new $20-million investment

davidlee1 Fri, 10/11/2019 - 11:52

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Freda Miller (left), a senior scientist at the Hospital for Sick Children, and University Professor Shana Kelley of the Leslie Dan Faculty of Pharmacy are leading two of the teams that Medicine by Design is funding

Ann Perry

Jovana Drinjakovic

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Faculty of Medicine

Gene Therapy

Institute of Biomaterials and Biomedical Engineering

Leslie Dan Faculty of Pharmacy

Medicine by Design

Meric Gertler

Regenerative Medicine

Research & Innovation

Stem Cells

Medicine by Design is strengthening the University of Toronto as a global leader in regenerative medicine with a new investment of as much as $20 million in research that will accelerate stem cell and gene therapy, advance understanding of how the body repairs itself and generate new technologies that will propel the field for decades.

The three-year awards will support as many as 12 multi-disciplinary research teams across U of T and its affiliated hospitals that are working at the convergence of engineering, medicine and life and physical sciences. These teams are leading the development of stem cell-based strategies to replace damaged heart and liver tissue and induce the body to self-repair damaged nerve and muscle, as well as tackling key challenges in the field such as the lack of control in producing specific tissue types from stem cells, with the goal of turning discoveries into new therapies, products and companies sooner.

“Medicine by Design has generated breakthroughs that are transforming regenerative medicine and sparking tremendous activity throughout Canada’s life sciences ecosystem,” said U of T President Meric Gertler. “This new investment will build on these advances, lay the foundation for translating these innovations into tangible benefits to patients and society, and advance Toronto’s position as the leading international centre of excellence in regenerative medicine for decades to come.”

Funded by a $114-million grant from the federal government’s Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative at U of T that is catalyzing transformative discoveries in regenerative medicine and accelerating them toward the clinic. It builds on decades of made-in-Canada excellence in regenerative medicine dating back to the discovery of stem cells in the early 1960s by Toronto researchers Drs. James Till and Ernest McCulloch.

This is the second time Medicine by Design has awarded large-scale funding for collaborative team projects. Research supported by the first round of Team Project awards (2016-2019) has already driven significant advances, including the first “map” of the human liver, which attracted further funding this year from the Chan Zuckerberg Initiative. Another Medicine by Design-funded team has developed “safe cells” that are programmed to be killed if they become harmful, a key advance in improving the utility of cell therapies.

Over the past three years, Medicine by Design-funded researchers have also launched 15 startups.

The new awards will build on these discoveries and continue to spur innovations that will push the field forward, said Michael Sefton, executive director of Medicine by Design.

“By bringing together leading investigators across disciplines and institutions to confront the most challenging problems in the field, we have created new collaborations that have fundamentally changed how the regenerative medicine community in Toronto works together,” said Sefton, a University Professor at the Institute of Biomaterials & Biomedical Engineering (IBBME) and the Michael E. Charles Professor in the department of chemical engineering and applied chemistry.

“These new projects all have significant potential to achieve transformative and globally competitive outcomes and advance groundbreaking discoveries toward the clinic, transforming how we treat many devastating diseases.”

One team led by Shana Kelley, a University Professor at the Leslie Dan Faculty of Pharmacy, is developing a suite of advanced tools to enable researchers to gain new insights into how stem cells differentiate into any specialized cell type.

Freda Miller, a senior scientist at the Hospital for Sick Children (SickKids), heads a team that is developing a platform that will enable the rapid identification and testing of signals that activate stem cells in muscle and brain to repair damaged tissue, which could transform the treatment of muscular dystrophy and demyelinating disorders, such as multiple sclerosis.

Restoring heart function after heart failure is the focus of another team led by Michael Laflamme, a senior scientist at the McEwen Stem Cell Institute at University Health Network (UHN).

“We’ve come a long way from deriving stem cell-derived heart muscle cells in the Petri dish to optimizing them now for eventual use in patients,” said Laflamme. “This massive effort would not have been possible without Medicine by Design, which brought us all together toward a common goal of finding a cure for heart failure.”

Medicine by Design selected projects for funding after an extensive evaluation process, which included consultation with the research community, external peer review and scientific and strategic advice from Medicine by Design’s scientific advisory board.

Other funded research includes projects aimed at:

Using stem cells to regenerate damaged livers, led by Gordon Keller, director of the McEwen Stem Cell Institute at UHN, in collaboration with Ian McGilvray, a senior scientist at the Toronto General Hospital Research Institute (TGHRI) and a transplant surgeon at UHN, Sonya MacParland, a scientist at TGHRI specializing in liver immunology, Molly Shoichet, a University Professor in the department of chemical engineering and applied chemistry, Axel Guenther, an associate professor in the department of mechanical and industrial engineering, Gary Bader, a professor in the Donnelly Centre for Cellular and Biomolecular Research, and Christine Bear, a senior scientist at SickKids.

Reprogramming brain cells to treat amyotrophic lateral sclerosis and stroke, led by Cindi Morshead, a professor and chair of the division of anatomy in the department of surgery, in collaboration with: Isabelle Aubert and Carol Schuurmans, senior scientists at the Sunnybrook Research Institute, Maryam Faiz, an assistant professor in the department of surgery, and Melanie Woodin, a professor in the department of cell and systems biology and dean of U of T’s Faculty of Arts & Science.

Understanding how immune cells function in healthy and damaged blood vessels, led by Clint Robbins, a scientist at TGHRI, in collaboration with Myron Cybulsky and Jason Fish, both senior scientists at TGHRI.

Studying how material exchange – a process whereby cellular material from transplanted cells is transferred to host cells – could play a role in improving outcomes of cell-based retinal therapy aimed at preserving and restoring sight. This project is led by Molly Shoichet in collaboration with Derek van der Kooy, a professor at the department of molecular genetics and the Donnelly Centre, Valerie Wallace, a senior scientist at the Krembil Research Institute at UHN, and Julie Lefebvre, a scientist at SickKids.

Additional projects, including those focused on the effect of aging on cardiac disease, organoids, diabetes and organ repair, are under review, with final decisions expected by December.

Advanced manufacturing supercluster invests in potentially life-saving gene therapies

rahul.kalvapalle — Thu, 22 Aug 2019 14:11:17 +0000

Advanced manufacturing supercluster invests in potentially life-saving gene therapies

rahul.kalvapalle Thu, 08/22/2019 - 10:11

Cutline

Navdeep Bains, the federal minister of innovation, science and economic development, speaks Wednesday at an event where the advanced manufacturing supercluster's first funded project, focused on genetic treatments, was announced (photo by Johnny Guatto)

Rahul Kalvapalle

Topic

Our Community

Advanced Manufacturing

Centre for the Commercialization of Regenerative Medicine

Faculty of Applied Science & Engineering

Gene Therapy

Regenerative Medicine

Research and Innovation

The organization that runs Canada’s advanced manufacturing supercluster – which includes the University of Toronto – has announced its first funded project: a consortium devoted to producing special viruses that can deliver genetic treatments to people suffering from late-stage cancers and rare genetic disorders.

Next Generation Manufacturing Canada (NGen), a not-for-profit that oversees the supercluster and includes Faculty of Applied Science & Engineering Dean Emerita Cristina Amon on its board, said it will contribute $1.89 million towards the project.

The project, led by Toronto-based company iVexSol Canada, will see iVexSol forge a partnership with the Centre for Commercialization of Regenerative Medicine (CCRM), which is hosted at U of T and counts Vice-President, Research and Innovation, and Strategic Initiatives Vivek Goel among its directors. Other partners include GE Healthcare and Vancouver-based biotech company Stemcell Technologies.

Its mission is to produce lentiviral vectors – retroviruses that are crucial to the development of cell and gene therapies to fight cancer and various genetic disorders – in far greater quantities and at a significantly lower cost than legacy methods by using iVexSol's clinically proven advanced manufacturing process.

Navdeep Bains, the federal minister of innovation, science and economic development, hailed the CCRM-linked project as an example of how the advanced manufacturing supercluster can drive potentially life-saving innovations.

“We all know someone who has had to battle cancer. This project and its results will give new hope to those family members, friends, the very people battling late-stage cancers,” Bains said during an event at the MaRS Discovery District on Wednesday.

“This project is an important first step for the game-changing work of the supercluster and will drive innovation in the treatment of diseases and genetic disorders once considered untreatable.”

Researchers work at the Centre for Commercialization of Regenerative Medicine, which supports the development of technologies focused on cell and gene therapies (photo courtesy of CCRM)

The advanced manufacturing supercluster is one of five superclusters announced by the federal government in early 2018. Superclusters – networks of companies, academic and research institutions and other innovation actors – are part of the government’s broader innovation strategy to invest in industries where Canadian companies are positioned to emerge as global leaders.

CCRM’s contribution to the gene therapies operation will be to provide manufacturing infrastructure and technical services.

Michael May, president and CEO of CCRM, said the organization was excited to offer its expertise to bring the project to fruition.

“This initiative aligns perfectly with CCRM’s purpose to revolutionize health care by solving the big problems in regenerative medicine, including cell and gene therapy,” said May, who earned his PhD in chemical engineering from U of T in 1998.

Bains noted that advanced manufacturing activities such as the lentiviral vector initiative have the potential to spawn economic benefits for generations.

“This is about making sure that innovation benefits Canadians and also creates economic growth and job opportunities,” Bains said.

“In Canada, we already have a strong footprint in manufacturing, and 10 per cent of the Canadian economy is linked to manufacturing. But today, it is advanced manufacturing that is revolutionizing how we produce goods, which are often products that promise to transform our lives.

“Globally, advanced manufacturing is an industry that’s valued in the billions of dollars – I’m talking hundreds of billions.”

The investment in iVexSol is expected to create over 450 jobs, while the NGen supercluster as a whole is estimated to create over 13,500 jobs and add more than $13.5 billion to the Canadian economy over the coming decade.

U of T scientists help discover how to turn off CRISPR

ullahnor — Fri, 09 Dec 2016 16:55:21 +0000

U of T scientists help discover how to turn off CRISPR ullahnor Fri, 12/09/2016 - 11:55

Heidi Singer

Author legacy

Heidi Singer

Subheadline

Researchers are part of an international team that has made gene editing safer and more precise, offering promise for new therapies

CRISPR genome editing is quickly revolutionizing biomedical research, but the new technology is not yet exact. The technique can inadvertently make excessive or unwanted changes in the genome and create off-target mutations, limiting safety and efficacy.

Now, researchers at the University of Toronto and University of Massachusetts Medical School have discovered the first known “off-switches” for CRISPR gene-editing activity, providing greater control and a much-needed “safety valve,” according to a new study featured on the cover of Cell.

The scientists found three proteins that block CRISPR, known as anti-CRISPRs.

U of T Faculty of Medicine's Alan Davidson, a professor of molecular genetics and biochemistry, and Karen Maxwell, an assistant professor of biochemistry, made the discovery with UMass researcher Erik J. Sontheimer.

“CRISPR is very powerful, but we have to be able to turn it off,” says Davidson. “This is a very fundamental addition to the toolbox which should give researchers more confidence to use gene editing.”

Professor Alan Davidson (left) and Assistant Professor Karen Maxwell are part of a research team that has discovered the first known “off-switches” for CRISPR gene editing

A simple and efficient way of editing the genome, CRISPR is changing biomedical research by making it far easier to inactivate or edit genes in a cell line for study. Work that used to take months or years to perform can now be done in weeks.

Scientists are developing CRISPR to target specific cell types, tissues or organs where a disease occurs. But sometimes, CRISPR hits the wrong target, causing unintended damage.

“CRISPR activity in these other cells, tissues or organs is at best useless and at worst a safety risk,” says Sontheimer. “But if you could build an off-switch that keeps Cas9 (the enzyme that cuts the DNA for editing) inactive everywhere except the intended target tissue, then the tissue specificity will be improved.”

The new paper not only identifies that “off switch” but it shows that CRISPR inhibitors have evolved naturally and can be identified and exploited.

The “off switch” will allow researchers to be more precise in their use of CRISPR. If they only want to use it during one stage of a cell’s life – such as when the DNA is replicating – they can turn it off during all other stages, reducing the chance of unwanted consequences.

A major way of delivering CRISPR into the body is through inactivated viruses that can be programmed to attach themselves to target cells. The challenge is that viruses can’t be engineered to be 100 per cent specific.

Researchers in muscular dystrophy, for example, want to target muscle cells. But a particular virus known for its ability to target muscle cells also attaches itself to liver cells, where it could cause unintended damage. The “off switch” could allow researchers to release “anti-CRISPR” proteins into the body to turn off CRISPR activity in liver cells, offering a new layer of protection against mistakes.

“Knowing we have a safety valve will allow people to develop many more uses for CRISPR,” says Maxwell. “Things that may have been too risky previously might be possible now.”

The “off switch” could be used across the board for any application of CRISPR technology to target specific cells or tissues. For the researchers, the next step is to widen the “off switch” to include other types of CRISPR systems.