平特五不中
The Foundational Projects funding program supports high-risk, early-stage projects with the potential to be game-changers in the fields of D2R鈥檚 areas of interest.
In the first funding cycle launched in 2024, 47 applications were received of which 17 received awards. View a summary of the review and selection process.
Funded project summaries
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Deep mutagenesis approaches to decode T cell receptor-antigen recognition
To maximize the potential of cancer vaccines, we must enhance the efficacy of T cells, key players in immune responses. Although current vaccines aim to trigger T cells against pathogens or cancer, ensuring they don鈥檛 mistakenly attack healthy cells remains a challenge. Moreover, the diversity of T cell receptors and tumor antigens complicates the design of effective and safe cancer vaccines. Our approach combines cutting-edge genome engineering with artificial intelligence to systematically screen for T cell receptors with optimal therapeutic properties. This method aims to crack the T cell receptor recognition code to expedite their optimization for individualized cancer vaccines.'
Principal Investigator: Raquel Cuella Martin (平特五不中)
Co-Investigator(s): Heather Melichar (平特五不中)
Collaborator(s): Benjamin Haley (Universit茅 de Montr茅al) and Li Xue (Radboud University)
Project duration: Two-year
D2R Axes: Clinical Research, Acceleration, and Implementation (Axis 4) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)
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pHREEDOM: A pH-Responsive probe to study endosomal escape for RNA delivery optimization and monitoring
Lipid nanoparticles (LNPs) are used to deliver gene therapies like mRNA and siRNA into cells. One current limitation with LNPs is that only a small amount of the genetic material actually reaches the cell interior. This is due to inefficient "endosomal escape," where LNPs get trapped in compartments inside the cell. To better understand and improve this process, we have developed a probe to track the pH inside LNPs as they move through cells. This tool will help us study how well LNPs release their cargo, leading to better designs for gene therapies and more efficient treatments in the future.
Principal Investigator: Pieter Cullis (University of British Columbia)
Co-Investigator(s): Anna Blakney (University of British Columbia)
Collaborator(s): Sabrina Leslie (UBC)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3)
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Engineering a circular RNA platform for cap-dependent translation
Messenger RNA, or mRNA, and its translation into protein lies at the heart of the central dogma of molecular biology. This proposal aims to engineer the first synthetic circular RNA platform to facilitate enhanced protein production and therapeutic applications.
Our long-term objectives include exploring the effects of diverse chemical modifications on circular RNA translation and utilizing novel synthetic chemical methods to produce these molecules tailored for human therapeutics.
Principal Investigator: Masad Damha (平特五不中)
Co-Investigator(s): Sidong Huang (平特五不中)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2)
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Modelling individual differences in patterns of epigenetic regulation
Advances in technologies combined with decreases in sequencing costs make it feasible to obtain multidimensional measures of epigenetic regulation. Since different aspects of regulation are captured from the range of epigenetic datatypes, in this grant we want to develop statistical methods that optimally combine this prolific, rich information to find key epigenetic patterns and how these patterns change with disease. We will develop these new methods using data generated from individuals before and after infection with influenza.
Principal Investigator: Celia Greenwood (Jewish General Hospital)
Co-Investigator(s): Jos茅e Dupuis (平特五不中) and Qihuang Zhang (平特五不中)
Project duration: Two-year
D2R Axes: Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5) Population Studies and Genomic Medicine (Axis 1)
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A first inclusive study on the ELSI aspects of RNA technologies and therapeutics
Our project will be the first to identify ethical, legal, and social issues raised by research and medical practice involving RNA technologies. We will use a 鈥淒elphi study鈥� method, in which experts share their views, respond to each other鈥檚 perspectives, and revise their own opinions until the group reaches consensus about the most important issues raised by RNA technology. The Delphi study will include scientists, clinicians, policymakers, bioethicists, legal scholars, and social scientists. We will also conduct a series of interviews to gather the perspectives of people representing vulnerable and marginalized groups who may be affected by these technologies.
Principal Investigator: Yann Joly (平特五不中)
Collaborator(s): Thomas Duchaine (平特五不中), Silvia Vidal (平特五不中) and Charles Dupras (Universit茅 de Montr茅al)
Project duration: Two-year
D2R Axes: Ethical, Socioeconomic, and Cultural Dimensions in Genomic Research (Axis 6) RNA Therapeutics (Axis 2)
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平特五不中 brand mRNA production
This project includes mRNA production technologies and student training aimed at establishing a Quebec-based production platform. Our goal is to provide researchers from diverse communities across Canada the ability to generate novel mRNA compositions and associated intellectual property for vaccines and protein replacement therapies. Two new discovery and production platforms will be evaluated for generating natural and chemically modified mRNAs. The production will combine chemical synthesis of RNA oligonucleotides and enzymatic reactions to generate mRNAs with highly diverse chemical structures aimed at enhancing mRNA potency and stability.
Principal Investigator: Nathan Luedtke (平特五不中)
Co-Investigator(s): Masad Damha (平特五不中) and Maureen McKeague (平特五不中)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3)
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B-cell derived extracellular vesicles with enriched miRNA contents that mitigate Th2 inflammation
The cost of care for individuals with severe asthma is alarmingly high, accounting for approximately 50% of the cost of asthma therapy in Canada. Current therapies like steroids have high toxicity, or only target individual inflammatory pathways. Biological therapies that potentially act on multiple pathways, with low toxicity, would be advantageous for severe asthma. Using our laboratory-produced B-Cell-derived extracellular vesicles (B2-EV), we simultaneously target multiple genes via a combination of miRNA. B2-EV will be tested using well-established preclinical mouse asthma models and spatial transcriptomics and proteomics to allow us to perform robust proof-of-concept experiments addressing the molecular basis for B2-EVs as a potential therapy for severe asthma.
Principal Investigator: Bruce Mazer (Research Institute of the 平特五不中 Health Centre)
Co-Investigator(s): Janusz Rak (Research Institute of the 平特五不中 Health Centre)
Collaborator(s): Yasser Riaz Al-Hosseini (平特五不中)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3)
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Enabling low-cost, massive-scale sequencing of antigen receptors for personalized immunotherapy
T cells identify and eliminate infected and cancer cells. They recognize diseased cells via their antigen receptor. Each T cell has a unique antigen receptor. There are hundreds of millions of T cells that patrol for diseased cells. Identifying antigen receptors is expensive and low throughput. We propose new technology that will allow for marked cost reductions and a massive increase in the number of antigen receptors that can be sequenced at once. This will have a broad impact on fundamental research and clinical applications that include testing the efficacy of emerging vaccines and expediting development of adoptive cell therapies.
Principal Investigator: Heather Melichar (平特五不中)
Co-Investigator(s): Judith Mandl (平特五不中) and Claudia Kleinman (Lady Davis Institute/平特五不中)
Collaborator(s): Benjamin Haley (Universit茅 de Montr茅al)
Project duration: Two-year
D2R Axes: Clinical Research, Acceleration, and Implementation (Axis 4) Population Studies and Genomic Medicine (Axis 1)
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RNA-targeting therapeutics to address antimicrobial resistance
RNA elements known as riboswitches control genes in bacteria and have not been found in humans. There are ongoing efforts to develop molecules that bind to riboswitches and alter gene expression, thereby impacting growth of pathogenic bacteria. Such molecules could become the next generation of antibiotics. However, there are many unsolved challenges in targeting riboswitches including host toxicity or antimicrobial resistance by accumulating mutations in the riboswitch. To overcome these challenges, we assembled a team to design riboswitch-targeting antibiotics. Using computer simulations and high-throughput assays, we will identify molecules that bind to and alter riboswitch shape, minimizing bacterial resistance
Principal Investigator: Nicolas Moitessier (平特五不中)
Co-Investigator(s): Maureen McKeague (平特五不中) and Anthony Mittermaier (平特五不中)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)
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Targeting an alternative oncogenic human epidermal growth factor receptor 2 splice isoform
Breast cancer is one of the most prevalent cancers afflicting human female populations. Despite the development of new therapies, morbidity and mortality from breast cancer remain critical issues due to acquisition of resistance to targeted therapies. Preliminary work from our group has shown that a variant of the HER2 oncogene known as HER2螖16 which is generated by alternative splicing resulting in skipping of Exon 16 is a potent oncogenic variant of HER2 capable of inducing multifocal metastatic in mammary tumors in Genetic Engineered Mouse Models (GEMMs). This form of HER2 lacks a small portion of its protein sequence in juxta-transmembrane region that facilitates dimerization of receptor leading to constitutive activation of HER2 tyrosine kinase. We have further shown that HER2螖16-derived tumors are highly resistant to the Trastuzumab-derived T-DM1 conjugated antibody and small molecule kinase inhibitors implicating this isoform as a potential determinant of resistance to HER2 targeted therapies. Finally, we recently showed that expression HER2螖16 can be detected in over 40% of HER2 positive breast cancer that is further correlated with poor clinical outcome. Despite the pressing need for reagents that specifically target this oncogenic HER2 splice isoform, to date no therapeutic agent is available that specifically targets this isoform. In this D2R proposal, we plan to identify and evaluate whether shRNAs targeting the splice junction could be used to target this oncogenic variant. In a related approach we will also identify key transacting factors regulating exon 16 skipping and assessing whether targeting these factors is a viable approach in preventing formation of the HER2螖16 oncogenic variant. Results from these studies could alter current clinical practice with HER2-targeted therapies.
Principal Investigator: William Muller (平特五不中)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)
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Defining the role of arginine methyltransferases in the regulation of intronic circular non-coding RNAs in diseases
Circular intronic RNAs (ciRNAs) are single-stranded, covalently closed RNAs derived from intron lariats circularized by 2鈥测��5鈥� junctions. Although their functions are still largely unexplored, aberrant expression of certain ciRNAs has been recently found in different human diseases. We discovered that the protein arginine methyltransferase 5 (PRMT5), a promising cancer drug target, plays an important role for the regulation of ciRNA expression. We will explore potential applications of PRMT5-regulated ciRNAs as non-invasive diagnostic and prognostic biomarkers for cancers and therapeutic reagents in human diseases such as Amyotropic Lateral Sclerosis (ALS) and cancer.
Principal Investigator: St茅phane Richard (Jewish General Hospital)
Project duration: Two-year
D2R Axes: Population Studies and Genomic Medicine (Axis 1) RNA Therapeutics (Axis 2)
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Single-cell and spatial profiling of RNA splicing to understand tumour heterogeneity
Abnormalities in how genes are processed, particularly through a process called splicing, play a key role in many diseases, including cancer. This project aims to develop new tools to study gene splicing at the single-cell level, which will help us better understand how it varies between individual cells in a tumor. By combining advanced sequencing technologies with novel computational algorithms, we will create a detailed map of splicing in kidney cancer cells. This approach will provide new insights into how splicing influences cell behavior in cancer and could lead to better understanding and treatments for this disease.
Principal Investigator: Hamed Shateri Najafabadi (平特五不中)
Co-Investigator(s): Yasser Riazalhosseini (平特五不中) and Ioannis Ragoussis (平特五不中)
Collaborator(s): Hani Goodarzi (University of California San Francisco)
Project duration: Two-year
D2R Axes: Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5) RNA Therapeutics (Axis 2)
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DNA nanoparticles for targeted therapy against acute myeloid leukemia
Acute myeloid leukemia (AML) is an aggressive blood cancer affecting around 1300 Canadians annually, with current therapies only curing 30% of patients. We have developed safe, controllable delivery vehicles for nucleic acid therapeutics, showing enhanced activity in many animal cancer models. We propose to develop nucleic acid therapies to target AML stem cells, which contribute to drug resistance and relapse. These structures will carry cancer therapeutics specifically to AML cells, sparing healthy cells and reducing toxic side effects, improving treatment efficacy and minimizing relapse.
Principal Investigator: Hanadi Sleiman (平特五不中)
Co-Investigator(s): Francois Mercier (平特五不中, Lady Davis Institute)
Project duration: Two-year
D2R Axes: Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3) RNA Therapeutics (Axis 2)
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Live imaging of mRNA 5鈥� cap interaction with translation initiation factors
In eukaryotic cells, the process of mRNA translation (making proteins from mRNA) begins when a specific protein complex called eIF4F interacts with the "cap" at the beginning of mRNA. Our research aims to examine how individual proteins involved in translation interact with the mRNA cap in real-time inside cells. Additionally, we will study how viral proteins, and other factors interfere with this process. The goal is to use this information to improve the design and effectiveness of future mRNA vaccines.
Principal Investigator: Nahum Sonenberg (平特五不中)
Co-Investigator(s): Maria Vera Ugalde (平特五不中) and Paul Wiseman (平特五不中)
Collaborator(s): Jacek Jemielity (University of Warsaw)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)
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Iron/siRNa-based dynamic delivery system boosting ferroptototic cell death in metastatic melanoma
Melanoma has traditionally been resistant to chemotherapy. In addition, acral and uveal melanoma subtypes are typically insensitive to immune checkpoint inhibitor therapeutics, where the 5-year survival rates are <30%. While, the 6.5-year survival rates (57-46%) have improved for patients with advanced cutaneous disease, many still do not respond, thereby necessitating the discovery and development of better therapeutics to significantly improve patient survival. Our goal for this proposal is to develop highly potent RNA-based therapeutics to introduce ferroptosis as a treatment modality for patients with unresectable melanoma for whom surgery is not an option or for whom checkpoint inhibitors are contraindications.
Principal Investigator: Maryam Tabrizian (平特五不中)
Co-Investigator(s): Danuta Radzioch (平特五不中), Sonia V. del Rinc贸n (平特五不中) and David Juncker (平特五不中)
Collaborator(s): Andr茅 Charette (Universit茅 de Montr茅al)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2)
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Dominant negative RNA: A novel approach to CFTR gene therapy
CF is a protein trafficking disease where the mutant, but otherwise functional gene is recognized by the cell鈥檚 quality control system. We have identified genes that correct the trafficking defect of mutant CFTR. We have shown that the inactive versions of these genes are the active agents in correcting mutant CFTR. The uniqueness of this approach is that that the inactive versions of the two genes correct the trafficking of mutant CFTR trafficking. We have shown that the shRNA in lentivirus versions of these genes can efficiently correct CFTR trafficking. We are currently refining their potential for CF gene therapy in cells from cystic fibrosis patients.
Principal Investigator: David Thomas (平特五不中)
Co-Investigator(s): John Hanrahan (平特五不中)
Collaborator(s): Michelle Scott (Universit茅 de Sherbrooke)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)
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Using native gut bacteria to release RNA therapeutics against intestinal nematode infections
Parasitic helminths inflict neglected tropical diseases upon humans and cause substantial losses in agriculture. Despite efforts, control interventions still face major challenges, exacerbated by the rapid emergence of drug resistance, particularly among livestock parasites. Therefore, it is imperative to explore alternative treatments for these infections. Leveraging emerging evidence of inter-kingdom extracellular vesicle exchange and our recent advancements in engineering native transgenic bacteria capable of engrafting in their original mammalian hosts, I aim to investigate the potential of bacteria-produced noncoding RNAs as anthelmintic agents. The objectives of this research endeavor include: i) Developing native E. coli tools to specifically target helminths both in vitro and in vivo at the site of infection, and ii) Identifying foreign noncoding RNA, originating from the host and the surrounding commensal microbiota, that interacts with worm messenger RNA, potentially regulating parasite gene expression. For modeling purposes in vitro, we will rely on Caenorhabditis elegans, and for in vitro and in vivo experiments, we will employ the mouse intestinal nematode parasite Heligmosomoides polygyrus bakeri. The innovation of this study lies in investigating the efficacy of miRNA targeting against helminth infections and utilizing commensal bacteria as carriers for anthelmintic molecules. This project harbors significant translational potential, aiming to address critical questions hindering progress in RNA therapeutics for parasitic diseases. Upon completion, this research will shed light on: i) the potential utility of antagonizing helminth miRNAs and other targets for treating or preventing helminth infections, thereby elucidating the role of miRNAs in the infection's development and maintenance, and ii) the viability of utilizing live bacteria therapeutics against helminth infections. This data will enrich our qualitative and quantitative understanding of EV and miRNA trafficking in the gut, serving as a cornerstone for future targeted investigations (e.g., on the molecules involved in spatiotemporal EV and RNA trafficking within worm tissue) and facilitating the acquisition of larger funding opportunities, such as CIHR and NIH grants.
Principal Investigator: Lucienne Tritten (平特五不中)
Collaborator(s): Amir Zarrinpar (University of California San Diego) and Oliver Rossbach (Justus-Liebig University of Giessen)
Project duration: Two-year
D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5) , Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3)
